KR20190142325A - Compounds That Inhibit MCL-1 Proteins - Google Patents

Abstract

또는 이의 입체이성질체; 및 이의 약제학적으로 허용 가능한 염, 및 이들 화합물을 함유하는 약제학적 조성물이 본원에서 제공된다. 본원에서 제공된 화합물 및 조성물은, 예를 들어, 암과 같은 질환 또는 병태의 치료에 사용될 수 있다.Provided herein are myeloid cell leukemia 1 protein (Mcl-1) inhibitors, methods of making the same, related pharmaceutical compositions, and methods of using the same. For example, a compound of formula I
Formula I;

Or stereoisomers thereof; And pharmaceutically acceptable salts thereof, and pharmaceutical compositions containing these compounds are provided herein. The compounds and compositions provided herein can be used, for example, in the treatment of diseases or conditions such as cancer.

Description

Compounds That Inhibit MCL-1 Proteins

Cross Reference to Related Applications

This application claims the benefit of US Patent Provisional Application No. 62 / 479,171, filed March 30, 2017, and US Patent Provisional Application No. 62 / 479,230, filed March 30, 2017, all of which are incorporated by reference in their entirety. It is incorporated by reference for all purposes as if fully set forth herein.

Technical Field

The present invention provides compounds that inhibit myeloid cell leukemia 1 protein (also abbreviated as Mcl-1, MCl-1, MCL-1 or MCL1); Using this compound to treat a disease or condition, such as cancer; And pharmaceutical compositions containing this compound.

One common feature of human cancer is overexpression of Mcl-1. Mcl-1 overexpression prevents cancer cells from undergoing cell death (apoptosis), allowing cells to survive despite widespread genetic damage.

Mcl-1 is a member of the Bcl-2 family of proteins. The Bcl-2 family includes apoptosis-inducing members (eg, BAX and BAK), which, when activated, form allogene-oligomers in the outer mitochondrial membrane, which cause pore formation and outflow of mitochondrial components, ie, apoptosis. Leads to steps. Anti-apoptotic members of the Bcl-2 family (eg Bcl-2, Bcl-XL and Mcl-1) block the activity of BAX and BAK. Other proteins (such as BID, BIM, BIK and BAD) exhibit additional regulatory functions.

Studies have shown that Mcl-1 inhibitors may be useful for treating cancer. MCl-1 is overexpressed in numerous cancers. See (Beroukhim et al. (2010) Nature 463, 899-90). Cancer cells, including the proliferation surrounding the Mcl-1 and Bcl-2-l-1 antiapoptotic genes, rely on the expression of these genes for survival. Beroukhim et al. Mcl-1 is a suitable target for the resumption of apoptosis in numerous cancer cells. G. Lessene, P. Czabotar and P. Colman, Nat. Rev. Drug. Discov., 2008, 7, 989-1000; C. Akgul Cell. Mol. Life Sci. Vol. 66, 2009; And Arthur M. Mandelin II, Richard M. Pope, Expert Opin. Ther. Targets (2007) 11 (3): 363-373.

New compositions and methods for preparing and formulating Mcl-1 inhibitors will be useful.

In one aspect, the invention provides a compound of formula (I)

Formula I;

Stereoisomers thereof, pharmaceutically acceptable salts thereof, or pharmaceutically acceptable salts of stereoisomers thereof,

In the formula,

Z is C or N;

Q is O, S, CR ^WA R ^WB , or NR ^a R ^b ;

W is CR ^WA R ^WB , —C═O or absent;

R ^WA and R ^WB are independently selected from H, -C _1-3 alkyl, -C _2-3 alkenyl, -C _2-3 alkynyl, halo, -OH, or -OC _1-3 alkyl;

로 표시되는 b는 시스(cis) 또는 트랜스(trans)일 수 있는 단일 또는 이중 화학 결합이고; symbol

B is a single or double chemical bond which may be cis or trans;

R ¹ is H, halo, C _1-6 alkylhalo, C _1-6 alkyl, C _2-6 alkenyl,-(CH ₂ CH ₂ O) _n R ^a , -SO ₂ R ^a , -C (= O) R ^a , -C (= 0) OR ^a , or -C (= 0) NR ^a R ^b ;

R ² is H, halo, C _1-6 haloalkyl, C _1-6 alkyl, OC _1-6 alkyl, C _2-6 alkenyl, C _1-6 alkenylene, -C _1-6 alkyl-OC _{1- 6} alkyl,-(CH ₂ CH ₂ O) _n R ^a , -SO ₂ R ^a , -C (= 0) R ^a , -C (= 0) OR ^a , -OC (= 0) R ^a , -C (═O) NR ^a R ^b , 6- to 12-membered aryl or heteroaryl, 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, or 3- to 12-membered cycloalkenyl, 3 -Membered to 12-membered monocyclic or bicyclic cycloalkyl, or 3-membered to 12-membered monocyclic or bicyclic heterocycloalkyl group, wherein the heteroaryl, spiroheterocycloalkyl or heterocycloalkyl group is independently from O, N or S With 1, 2, 3 or 4 heteroatoms selected, the cycloalkyl, spirocycloalkyl, spirocyclocycloalkyl, and heterocycloalkyl groups can comprise C═O groups, further spiroheterocycloalkyl and heterocycloalkyl groups Is S = O or SO ² May include;

R ³ is H, —C _1-6 alkylhalo, —C _1-6 alkyl, —C _2-6 alkenyl, — (CH ₂ CH ₂ O) _n R ^a , —C (═O) R ^a , -C (= 0) OR ^a , or -C (= 0) NR ^a R ^b ;

R ^2B , R ^2C , R ⁴ , R ⁵ , R ⁶ , R ⁷ , and R ⁸ are each H, halo, —C _1-6 haloalkyl, —C _1-6 alkyl, —OC _1-6 alkyl, — C _2-6 alkenyl, -C _1-6 alkyl, -OC _{1-6 alkyl, - (CH 2 CH 2 O} ) n R a, -SO 2 R a, -C (= O) R a, - C ( = O) OR ^a , -OC (= O) R ^a , -C (= O) NR ^a R ^b , 6- to 12-membered aryl or heteroaryl, 5- to 12-membered spirocycloalkyl or spiro Heteroaryl, independently selected from heterocycloalkyl, 3- to 12-membered cycloalkenyl, 3- to 12-membered monocyclic or bicyclic cycloalkyl, or 3- to 12-membered monocyclic or bicyclic heterocycloalkyl group, heteroaryl , The spiroheterocycloalkyl and heterocycloalkyl groups have 1, 2, 3 or 4 heteroatoms independently selected from O, N or S, and the cycloalkyl, spirocycloalkyl, spirocyclocycloalkyl, and heterocycloalkyl groups are C May comprise a ═O group, and further comprises spiroheterocycloalkyl and hetero Claw alkyl group may include a S = O or SO _2, and;

Alternatively, R ³ and R ⁴ together with the atoms to which they are attached form a 5-membered to 12-membered ring, wherein in addition to the S and N atoms present in the ring, a heteroatom selected from N, O or S atoms is optionally To form a containing ring, the ring may optionally contain at least one double bond, and the ring may be substituted with 0, 1, 2, or 3 R ^3A substituents;

R ^3A is H, halo, -OH, C _1-6 haloalkyl, C _1-6 alkyl, OC _1-6 alkyl, C _2-6 alkenyl, -C _1-6 alkyl -OC _1-6 alkyl,- (CH ₂ CH ₂ O) _n R ^a , -SO ₂ R ^a , -C (= 0) R ^a, -C (= 0) OR ^a , -OC (= 0) R ^a , or -C (= 0) ) NR ^a R ^b ;

Each of R ^4A , R ^5A , R ^6A , R ^7A , and R ^8A is independently selected from H, OH, halo, or —C _1-6 alkyl;

R ^7A and R ^8A are absent when b is a double chemical bond;

Alternatively, R ⁷ and R ⁸ may form a 3- to 12-membered ring together with the atoms to which they are attached, and the ring may optionally contain at least one double bond;

R ⁹ is H, OH,-(= O), -C _1-6 haloalkyl, -C _1-6 alkyl, -C _1-6 alkenylene,-(CH ₂ CH ₂ O) _n R ^a , -C (═O) R ^a, —C (═O) OR ^a , —C (═O) NR ^a R ^b , —C _1-6 alkyl-OC _1-6 alkyl, cyano, 6- to 12-membered Aryl or heteroaryl, 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, 3- to 12-membered cycloalkenyl, 3- to 12-membered monocyclic or bicyclic cycloalkyl, or 3-membered to Independently selected from a 12-membered monocyclic or bicyclic heterocycloalkyl group, a heteroaryl, spiroheterocycloalkyl or heterocycloalkyl group has 1, 2, 3 or 4 heteroatoms independently selected from O, N or S, and cyclo Alkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkyl groups may comprise C═O groups, and further spiroheterocycloalkyl and heterocycloalkyl groups may comprise S═O or SO ₂ ;

R ^9A is H, -OH, halo, cyano, -C _1-6 haloalkyl, -C _1-6 alkyl, -C ₂ -C ₆ alkenyl, -C ₂ -C ₆ alkynyl, -C _{1- 6} alkenylene,-(CH ₂ CH ₂ O) _n R ^a , -P (= O) OR ^a OR ^b , -CSR ^a , -CS (= O) R ^a , -SR ^a , -SOR ^a , -OSO ₂ R ^a , -SO ₂ R ^a ,-(CH ₂ CH ₂ O) _n CH ₃ ,-(= O), -C (= O), -C (= O) R ^a , -C (= O) OR ^a , -C (= 0) NR ^a R ^b , -CH ₂ -NR ^a R ^b , -NR ^a R ^b , -C _1-6 alkyl-OC _1-6 alkyl, -OC _1-6 alkyl,- OC _1-6 alkyl-OC _1-6 alkyl, phenyl, 6- to 12-membered aryl, 6- to 12-membered heteroaryl, 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, 3 Independently selected from -membered to 12-membered cycloalkenyl, 3-membered to 12-membered monocyclic or bicyclic cycloalkyl, or 3-membered to 12-membered monocyclic or bicyclic heterocycloalkyl group, heteroaryl, spiroheterocycloalkyl And the heterocycloalkyl group has 1, 2, 3 or 4 heteroatoms independently selected from O, N or S, cycloal , Spiro cycloalkyl, spiro-heterocycloalkyl, and heterocycloalkyl group is further number, and comprise a group may contain a double bond and the C = O spiro heterocycloalkyl and heterocycloalkyl group contains S = O or SO ₂ Can do it;

R ^9A is not H when W is absent;

The aryl, heteroaryl, cycloalkyl, heterocycloalkyl, spirocycloalkyl and ^{spirterocycloalkyl} groups of the R ^9A substituent are unsubstituted or substituted with OH, halo, -NR ^c R ^d , -C _1-6 alkyl, -C ₂ -C ₆ alkenyl, -C ₂ -C ₆ alkynyl, -OC _1-6 alkyl, -C _1-6 alkyl-OH, -C _1-6 alkyl-OC _1-6 alkyl, C _1-6 haloalkyl,- O-haloC _1-6 alkyl, -SO ₂ R ^c , -CN, -C (= 0) NR ^c R ^d , -C (= 0) R ^c , -OC (= 0) R ^a , -C ( = O) OR ^c , 6- to 12-membered aryl, 6- to 12-membered heteroaryl, 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, 3- to 12-membered cycloal May be substituted with 1, 2, 3 or 4 R ¹⁰ substituents independently selected from kenyl, 3- to 12-membered monocyclic or bicyclic cycloalkyl, or 3- to 12-membered monocyclic or bicyclic heterocycloalkyl groups, Heteroaryl, spiroheterocycloalkyl, and heterocycloalkyl groups are 0, independently selected from O, N or S, Having 1, 2, 3 or 4 heteroatoms, the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkyl groups can comprise C═O groups, and further the spiroheterocycloalkyl and heterocycloalkyl groups May comprise S═O or SO ₂ ;

Alternatively, R ⁷ and R ^9A together with the atoms to which they are attached may form a 3-membered to 12-membered ring, and the ring may optionally contain at least one double bond;

Alternatively, R ⁹ and R ^9A form a 3-membered to 12-membered monocyclic or bicyclic ring together with Q, W and C to which W and Q bond, a hetero group other than Q selected from N, O or S A ring optionally containing atoms may be formed, the ring may contain a double bond, the ring may optionally include a C═O group, and further the ring may be substituted by 1, 2, or 3 R ¹¹ substituents May be optionally substituted;

R ¹¹ is H, -OH, halo, -C _1-6 alkyl, -OC _1-6 alkyl, -C _1-6 alkyl-OH, -C _1-6 alkyl-OC _1-6 alkyl, -C _{1- 6} haloalkyl, -O-haloC _1-6 alkyl, -SO ₂ R ^c , -CN, -NR ^c R ^d , -C (= 0) NR ^c R ^d , -C (= 0) R ^c ,- OC (= 0) R ^c , -C (= 0) OR ^c , 6- to 12-membered aryl or heteroaryl, 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, 3- to 12 Independently selected from -membered cycloalkenyl, 3-membered to 12-membered monocyclic or bicyclic cycloalkyl, or 3-membered to 12-membered monocyclic or bicyclic heterocycloalkyl group, heteroaryl, spiroheterocycloalkyl, and heterocyclo The alkyl group has 1, 2, 3 or 4 heteroatoms independently selected from O, N or S, and the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkyl groups can comprise double bonds and cyclo Alkyl, spirocycloalkyl, spiroheterocycloalkyl, And the heterocycloalkyl group may comprise a C═O group, and further the spiroheterocycloalkyl and heterocycloalkyl group may comprise S═O or SO ₂ ;

R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ^4A , R ^5A , R ^6A , R ^7A , R ^8A , R ^9A C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl and —OC _1-6 alkyl of any one of the R ^WA and R ^WB substituents may be unsubstituted or substituted with OH, —OC _1-6 alkyl, -C _1-6 alkyl-OC _1-6 alkyl, halo, -O-haloC _1-6 alkyl, -CN, -NR ^a R ^b ,-(NR ^a R ^b R ^c ) _n , -OSO ₂ R ^a , -SO ₂ R ^a ,-(CH ₂ CH ₂ O) _n CH ₃ ,-(= O), -C (= O), -C (= O) R ^a , -OC (= O) R ^a , -C (= 0) OR ^a , -C (= 0) NR ^a R ^b , -O-SiR ^a R ^b R ^c , -SiR ^a R ^b R ^c , -O- (3- to 10-membered hetero Cycloalkyl), 6-membered to 12-membered aryl or heteroaryl, 5-membered to 12-membered spirocycloalkyl or spiroheterocycloalkyl, 3-membered to 12-membered cycloalkenyl, 3-membered to 12-membered Monocyclic or bicyclic cycloalkyl, or substituted by 1, 2 or 3 R 12 substituents independently selected from 3- to 12-membered monocyclic or bicyclic heterocycloalkyl groups, heteroaryl, spi Heterocycloalkyl and heterocycloalkyl groups have 1, 2, 3 or 4 heteroatoms independently selected from O, N or S, and cycloalkyl, spirocycloalkyl, spirocyclocycloalkyl, and heterocycloalkyl groups are C═O Groups, and further, the spiroheterocycloalkyl and heterocycloalkyl groups may comprise S═O or SO ₂ ;

R ² , R ⁴ , R ⁵ , Aryl, heteroaryl, cycloalkyl, heterocycloalkyl, spirocycloalkyl and any one of R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ^9A , R ¹⁰ , R ¹¹ , R ¹² , R ^WA and R ^WB substituents and Spiroheterocycloalkyl groups are unsubstituted or substituted with OH, halo, -NR ^c R ^d , -C _1-6 alkyl, -OC _1-6 alkyl, -C _1-6 alkyl-OH, -C _1-6 alkyl-OC _{1 -6} alkyl, C _1-6 haloalkyl, -O-haloC _1-6 alkyl, -SO ₂ R ^c , -CN, -C (= 0) NR ^c R ^d , -C (= 0) R ^c , -OC (= 0) R ^a , -C (= 0) OR ^c , 6- to 12-membered aryl or heteroaryl, 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, 3-membered to With 1, 2, 3 or 4 R ¹³ substituents independently selected from 12-membered cycloalkenyl, 3- to 12-membered monocyclic or bicyclic cycloalkyl, or 3-membered to 12-membered monocyclic or bicyclic heterocycloalkyl group may be substituted, a heteroaryl group, spiro-heterocycloalkyl, heteroaryl, and cycloalkyl group of R ¹³ is O, N or S robu Independently has a selected one, two, three or four heteroatoms, heterocycloalkyl group of R ¹³ cycloalkyl, spiro cycloalkyl, and spiro heterocycloalkyl group or R ¹³ is additionally can comprise a C = O, Spiroheterocycloalkyl and heterocycloalkyl groups may comprise S═O or SO ₂ ;

Each of R ^a , R ^b , R ^c , and R ^d is independently hydrogen, OH, —C _1-6 alkyl, —C _2-6 alkenyl, —C _2-6 alkynyl, —C _1-6 alkyl -NR ¹⁴ R ¹⁴ , -NR ¹⁴ R ¹⁴ , -SO ₂ R ¹⁴ ,-(CH ₂ CH ₂ O) _n CH ₃ ,-(= O), -C (= O) R ¹⁴ , -OC (= O ) R ¹⁴ , -C (= 0) OR ¹⁴ , -C (= 0) NR ¹⁴ R ¹⁴ , -C _1-6 haloalkyl, -O-haloC _1-6 alkyl, -C _1-6 alkyl-OC _1-6 alkyl, benzyl, phenyl, -C _1-6 alkyl C (= 0) OH, -C _1-6 alkyl-C (= 0) -OC _1-6 alkyl, -C _1-6 alkyl-cycloalkyl , -C _1-6 alkyl-heterocycloalkyl, -C _1-6 alkyl-6- to 10-membered aryl, -C _1-6 alkyl-6- to 10-membered heteroaryl, 6- to 12 -Membered aryl or heteroaryl, 5-membered to 12-membered spirocycloalkyl or spiroheterocycloalkyl, or 3-membered to 12-membered cycloalkenyl, 3-membered to 12-membered monocyclic or bicyclic cycloalkyl, or 3 -membered to 12-membered monocyclic or bicyclic heteroaryl and a cycloalkyl group, a heteroaryl group, spiro-heterocycloalkyl, heterocycloalkyl-alkyl or -C _1-6 alkyl- Interrogating cycloalkyl group O, N, or independently selected from one, two, three or with four heteroatoms from S, cycloalkyl of R ^a, R ^b, R ^c, and R ^d, spiro cycloalkyl, spiro-heterocycloalkyl The heterocycloalkyl group of the heterocycloalkyl group or -C _1-6 alkyl-heterocycloalkyl group may include a double bond and may include a C═O group, and spiroheterocycloalkyl or heterocycloalkyl may be S═O or SO May comprise ₂ ;

Of R ^a, R ^b, R ^c, and R ^d of the alkyl, aryl, heteroaryl, spiro cycloalkyl, spiro-heterocycloalkyl, cycloalkyl, or heterocycloalkyl group, and R ^a, R ^b, R ^c, and R ^d The heterocycloalkyl group of a -C _1-6 alkyl-heterocycloalkyl group may be unsubstituted or substituted with 1, 2, 3, or 4 R ¹⁴ substituents, each R ¹⁴ being H, -OH, -N = N = N, halo, -C _1-6 alkyl, -C _1-6 haloalkyl, -OC _1-6 alkyl, -C _1-6 alkyl-OC _1-6 alkyl, -C _1-6 haloalkyl, -O -HaloC _1-6 alkyl, phenyl, tolyl, -C (= 0) C _1-6 alkyl, -C (= 0) OC _1-6 alkyl, N (CH ₃ ) ₂ or -SO ₂ -N (CH ₃ ) independently selected from ₂ ;

n is independently at each occurrence an integer of 1, 2, 3 or 4.

In another embodiment, the present invention provides a compound of Formula I '

Formula I ';

Stereoisomers thereof, pharmaceutically acceptable salts thereof, or pharmaceutically acceptable salts of stereoisomers thereof,

In the formula,

Z is C or N;

Q is O or S;

W is CR ^WA R ^WB or —C═O;

R ^WA and R ^WB are independently selected from H, -C _1-3 alkyl, halo, -OH, or -OC _1-3 alkyl;

로 표시되는 b는 시스 또는 트랜스일 수 있는 단일 또는 이중 화학 결합이고; symbol

B is a single or double chemical bond which may be cis or trans;

R ¹ is H, halo, C _1-6 alkylhalo, C _1-6 alkyl,-(CH ₂ CH ₂ O) _n R ^a , -SO ₂ R ^a , -C (= O) R ^a , -C Independently selected from (═O) OR ^a , or —C (═O) NR ^a R ^b ;

R ² is H, halo, C _1-6 haloalkyl, C _1-6 alkyl, OC _1-6 alkyl, C _2-6 alkenyl, -C _1-6 alkyl-OC _1-6 alkyl,-(CH ₂ CH ₂ O) _n R ^a , -SO ₂ R ^a , -C (= 0) R ^a , -C (= 0) OR ^a , -OC (= 0) R ^a , or -C (= 0) NR ^a R ^b ;

R ³ is H, —C _1-6 alkylhalo, —C _1-6 alkyl, —C _2-6 alkenyl, — (CH ₂ CH ₂ O) _n R ^a , —C (═O) R ^a , Independently from -C (= 0) OR ^a , or -C (= 0) NR ^a R ^b ;

R ⁴ , R ⁵ , R ⁶ , R ⁷ , and R ⁸ are each H, halo, -C _1-6 haloalkyl, -C _1-6 alkyl, -OC _1-6 alkyl, -C _2-6 alkenyl , -C _1-6 alkyl-OC _1-6 alkyl,-(CH ₂ CH ₂ O) _n R ^a , -SO ₂ R ^a , -C (= O) R ^a, -C (= O) OR ^a , -OC (= 0) R ^a , -C (= 0) NR ^a R ^b , 6- to 12-membered aryl or heteroaryl, 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, 3- Independently selected from membered to 12-membered cycloalkenyl, 3-membered to 12-membered monocyclic or bicyclic cycloalkyl, or 3-membered to 12-membered monocyclic or bicyclic heterocycloalkyl group, heteroaryl, spiroheterocycloalkyl and Heterocycloalkyl groups have 1, 2, 3 or 4 heteroatoms independently selected from O, N or S, and cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkyl groups can include C═O groups And further spiroheterocycloalkyl and heterocycloalkyl It may comprise a S = O or SO _2, and;

Alternatively, R ³ and R ⁴ together with the atoms to which they are attached form a 5-membered to 12-membered ring, wherein in addition to the S and N atoms present in the ring, a heteroatom selected from N, O or S atoms is optionally To form a containing ring, the ring may optionally contain at least one double bond, and the ring may be substituted with 0, 1, 2, or 3 R ^3A substituents;

R ^3A is H, halo, -OH, C _1-6 haloalkyl, C _1-6 alkyl, OC _1-6 alkyl, C _2-6 alkenyl, -C _1-6 alkyl -OC _1-6 alkyl,- (CH ₂ CH ₂ O) _n R ^a , -SO ₂ R ^a , -C (= 0) R ^a , -C (= 0) OR ^a , -OC (= 0) R ^a , or -C (= 0) ) NR ^a R ^b independently;

Each of R ^4A , R ^5A , R ^6A , R ^7A , and R ^8A is independently selected from H, OH, halo, or —C _1-6 alkyl;

R ^7A and R ^8A are absent when b is a double chemical bond;

R ⁹ is H, -C _1-6 haloalkyl, -C _1-6 alkyl, -C _2-6 alkenyl, -C _2-6 alkynyl,-(CH ₂ CH ₂ O) _n R ^a , -C (═O) R ^a , —C (═O) OR ^a , —C (═O) NR ^a R ^b , —C _1-6 alkyl-OC _1-6 alkyl, 6- to 12-membered aryl or hetero Aryl, 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, 3- to 12-membered cycloalkenyl, 3- to 12-membered monocyclic or bicyclic cycloalkyl, or 3- to 12-membered Independently selected from monocyclic or bicyclic heterocycloalkyl groups, heteroaryl, spiroheterocycloalkyl or heterocycloalkyl groups have 1, 2, 3 or 4 heteroatoms independently selected from O, N or S, cycloalkyl, spiro Cycloalkyl, spiroheterocycloalkyl, and heterocycloalkyl groups may comprise C═O groups, and further, spirohterocycloalkyl and heterocycloalkyl groups may comprise S═O or SO ₂ ;

R ^9A is H, —C _1-6 haloalkyl, —C _1-6 alkyl, —C _2-6 alkenyl, —C _2-6 alkynyl, — (CH ₂ CH ₂ O) _n R ^a , -SO ₂ R ^a , -C (= O) R ^a , -C (= O) OR ^a , -C (= O) NR ^a R ^b , -NR ^a R ^b , -N = N = N, -C _{1- 6} alkyl-OC _1-6 alkyl, 6- to 12-membered aryl, 6- to 12-membered heteroaryl, 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, 3- to 12- Independently selected from a membered cycloalkenyl, 3-membered to 12-membered monocyclic or bicyclic cycloalkyl, or 3-membered to 12-membered monocyclic or bicyclic heterocycloalkyl group, and heteroaryl, spiroheterocycloalkyl and heterocycloalkyl group The cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkyl groups having 1, 2, 3 or 4 heteroatoms independently selected from O, N or S may further comprise C═O groups, further Spiroheterocycloalkyl and heterocycloalkyl groups are S═O or SO May comprise ₂ ;

The aryl, heteroaryl, cycloalkyl, heterocycloalkyl, spirocycloalkyl and ^{spirterocycloalkyl} groups of the R ^9A substituent are unsubstituted or substituted with OH, halo, -NR ^c R ^d , -C _1-6 alkyl, -C ₂ -C ₆ alkenyl, -C ₂ -C ₆ alkynyl, -OC _1-6 alkyl, -C _1-6 alkyl-OH, -C _1-6 alkyl-OC _1-6 alkyl, C _1-6 haloalkyl,- O-haloC _1-6 alkyl, -SO ₂ R ^c , -CN, -C (= 0) NR ^c R ^d , -C (= 0) R ^c , -OC (= 0) R ^a , -C ( = O) OR ^c , 6- to 12-membered aryl, 6- to 12-membered heteroaryl, 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, 3- to 12-membered cycloal May be substituted with 1, 2, 3 or 4 R ¹⁰ substituents independently selected from kenyl, 3- to 12-membered monocyclic or bicyclic cycloalkyl, or 3- to 12-membered monocyclic or bicyclic heterocycloalkyl groups, Heteroaryl, spiroheterocycloalkyl, and heterocycloalkyl groups are 0, independently selected from O, N or S, Having 1, 2, 3 or 4 heteroatoms, the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkyl groups can comprise C═O groups, and further the spiroheterocycloalkyl and heterocycloalkyl groups May comprise S═O or SO ₂ ;

Alternatively, R ⁹ and R ^9A form a 3-membered to 12-membered monocyclic or bicyclic ring together with Q, W and C to which W and Q bond, a hetero group other than Q selected from N, O or S A ring optionally containing atoms may be formed, the ring may contain a double bond, the ring may optionally include a C═O group, and further the ring may be substituted by 1, 2, or 3 R ¹¹ substituents May be optionally substituted;

R ¹¹ is —OH, halo, —NR ^c R ^d , —C _1-6 alkyl, —OC _1-6 alkyl, —C _1-6 alkyl-OH, —C _1-6 alkyl-OC _1-6 alkyl, -C _1-6 haloalkyl, -O-haloC _1-6 alkyl, -SO ₂ R ^c , -CN, -C (= 0) NR ^c R ^d , -C (= 0) R ^c , -OC ( ═O) R ^a , —C (═O) OR ^c , 6- to 12-membered aryl or heteroaryl, 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, 3- to 12-membered Independently selected from cycloalkenyl, 3-membered to 12-membered monocyclic or bicyclic cycloalkyl, or 3-membered to 12-membered monocyclic or bicyclic heterocycloalkyl group, heteroaryl, spiroheterocycloalkyl, and heterocycloalkyl group The cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkyl groups having 1, 2, 3 or 4 heteroatoms independently selected from O, N or S may further comprise C═O groups, further Spiroheterocycloalkyl and heterocycloalkyl groups are S = O or It may contain SO _2, and;

R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ^4A , R ^5A , R ^6A , R ^7A , R ^8A , and R The —C _1-6 alkyl of any of the ^9A substituents may be unsubstituted or substituted with OH, —OC _1-6 alkyl, —C _1-6 alkyl-OC _1-6 alkyl, halo, —O-haloC _1-6 alkyl, -CN, -NR ^a R ^b ,-(NR ^a R ^b R ^c ) _n , -SO ₂ R ^a ,-(CH ₂ CH ₂ O) _n CH ₃ , (= O), -C (= O), -C (= O) R ^a , -OC (= O) R ^a , -C (= O) OR ^a , -C (= O) NR ^a R ^b , -O-SiR ^a R ^b R ^c , -O -(3- to 12-membered heterocycloalkyl), phenyl, 6- to 12-membered aryl or heteroaryl, 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, 3- to 12- Substituted by 1, 2 or 3 R ¹² substituents independently selected from membered cycloalkenyl, 3-membered to 12-membered monocyclic or bicyclic cycloalkyl, or 3-membered to 12-membered monocyclic or bicyclic heterocycloalkyl group, Heteroaryls, spiroheterocycloalkyls and heterocycloalkyl groups are derived from O, N or S The cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkyl groups having one, two, three or four heteroatoms selected, may comprise a C═O group, and further, spiroheterocycloalkyl and hetero Cycloalkyl groups may include S═O or SO ₂ ;

R ² , R ⁴ , R ⁵ , The aryl, heteroaryl, cycloalkyl, heterocycloalkyl, spirocycloalkyl and spiroheterocycloalkyl groups of any one of the R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , and R ¹² substituents are unsubstituted or OH, halo, -C _1-6 alkyl, -OC _1-6 alkyl, -C _1-6 alkyl-OH, -C _1-6 alkyl-OC _1-6 alkyl, C _1-6 haloalkyl, -O- HaloC _1-6 alkyl, -SO ₂ R ^c , -NR ^c R ^d , -CN, -C (= 0) NR ^c R ^d , -C (= 0) R ^c , -OC (= 0) R ^a , -C (= 0) OR ^c , -B (OH) ₂ , 6- to 12-membered aryl or heteroaryl, 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, 3- to 12 Substituted with 1, 2, 3 or 4 R ¹³ substituents independently selected from -membered cycloalkenyl, 3- to 12-membered monocyclic or bicyclic cycloalkyl, or 3- to 12-membered monocyclic or bicyclic heterocycloalkyl groups Wherein the heteroaryl, spiroheterocycloalkyl, and heterocycloalkyl groups are independently from O, N or S With 1, 2, 3 or 4 heteroatoms selected, the cycloalkyl, spirocycloalkyl, spirocyclocycloalkyl, and heterocycloalkyl groups can comprise C═O groups, further spiroheterocycloalkyl and heterocycloalkyl groups May comprise S═O or SO ₂ ;

Each of R ^a , R ^b , R ^c , and R ^d is independently hydrogen, OH, —C _1-6 alkyl, —C _1-6 alkenyl, —C _2-6 alkynyl, —C _1-6 alkyl -NR ¹⁴ R ¹⁴ , NR ¹⁴ R ¹⁴ , -SO ₂ R ¹⁴ ,-(CH ₂ CH ₂ O) _n CH ₃ , (= O), -C (= O) R ¹⁴ , -OC (= O) R ¹⁴ , -C (= 0) OR ¹⁴ _, -C (= 0) NR ¹⁴ R ¹⁴ , C _1-6 haloalkyl, -O-haloC _1-6 alkyl, -C _1-6 alkyl-OC _1-6 Alkyl, -C _1-6 alkyl-OH, benzyl, phenyl, -C _1-6 alkyl-3-membered to 12-membered heterocycloalkyl, 6-membered to 12-membered aryl or heteroaryl, 5-membered to 12 -Membered spirocycloalkyl or spiroheterocycloalkyl, or 3-membered to 12-membered cycloalkenyl, 3-membered to 12-membered monocyclic or bicyclic cycloalkyl, or 3-membered to 12-membered monocyclic or bicyclic heterocycloalkyl group and, heteroaryl, spiro-heterocycloalkyl, heteroaryl, and cycloalkyl and -C _1-6 alkyl-heterocycloalkyl group in heterocycloalkyl group is O, N or S independently selected from 1, 2, 3 or 4 hetero Has characters, cycloalkyl, spiro cycloalkyl, spiro-heterocycloalkyl, heterocycloalkyl, and -C _1-6 alkyl-heterocycloalkyl group in heterocycloalkyl group may include a group C = O, spiro-heterocycloalkyl additionally And heterocycloalkyl groups can include S═O or SO ₂ ;

Heterocycloalkyl groups of alkyl, aryl, heteroaryl, spirocycloalkyl, spiroheterocycloalkyl, cycloalkyl, heterocycloalkyl and -C _1-6 alkyl-heterocycloalkyl groups of R ^a , R ^b , R ^c , and R ^d Is unsubstituted or substituted with H, OH, -N = N = N, halo, -C _1-6 alkyl, -OC _1-6 alkyl, C _1-6 haloalkyl, -O-haloC _1-6 alkyl, phenyl, 1, 2, 3, or 4 independently selected from tolyl, -C (O) C _1-6 alkyl, -C (O) OCH ₃ , -SO ₂ -phenyl, or -SO ₂ -N (CH ₃ ) ₂ May be substituted with four R ¹⁴ substituents;

n is independently at each occurrence an integer of 1, 2, 3 or 4.

In another embodiment, the compound of formula (I ') is formula (II'a)

Formula II'a;

Or stereoisomers thereof, pharmaceutically acceptable salts thereof, or pharmaceutically acceptable salts of stereoisomers thereof.

Another aspect of the invention provides a pharmaceutical composition comprising the composition of any one of the embodiments or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.

Another aspect of the invention provides a method of treating cancer. Such method comprises: administering to a patient in need thereof a therapeutically effective amount of a composition of any of the embodiments or a pharmaceutically acceptable salt thereof. In some such methods, the cancer is a hematologic malignancy. In some such methods, the cancer is selected from the group consisting of breast cancer, colon cancer, skin cancer, melanoma, ovarian cancer, kidney cancer, lung cancer, non-small cell lung cancer, lymphoma, non-Hodgkin's lymphoma, myeloma, multiple myeloma, leukemia and acute myeloid leukemia do. In some other methods, the cancer is multiple myeloma. In some other methods, the cancer is acute myeloid leukemia. In some other methods, the cancer is non-Hodgkin's lymphoma. In another embodiment, the method further comprises administering to the patient in need thereof a therapeutically effective amount of a further pharmaceutically active compound. For example, in some such methods, the additional pharmaceutically active compound is carfilzomib. In another method, the additional pharmaceutically active compound is venetoclax. In another method, the additional pharmaceutically active compound is cytarabine.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Methods and materials for use in the present disclosure are described herein; Other suitable methods and materials known in the art may be used. The materials, methods, and examples are illustrative only and not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control.

Other features and advantages of the disclosure will be apparent from the following detailed description, drawings, and claims.

1 shows that the efficacy of Example 1 is superior to reference compound 1 in the tumor PD model. Female athymic nude mice inoculated with OPM-2 luciferase cells were orally administered with both compounds.
FIG. 2 shows that the in vivo efficacy of Example 2 and Example 3 is superior to Reference Compound 1 in the tumor PD model. Female athymic nude mice inoculated with OPM-2 luciferase cells were orally administered with both compounds.
3 shows superior in vivo efficacy of Example 4 compared to Reference Compound 1 in tumor PD models. Female athymic nude mice inoculated with OPM-2 luciferase cells were orally administered with both compounds.
4 shows superior in vivo efficacy of Example 10 compared to Reference Compound 1 in tumor PD models. Female athymic nude mice inoculated with OPM-2 luciferase cells were orally administered with both compounds.
5 shows superior in vivo efficacy of Example 11 compared to Reference Compound 1 in tumor PD models. Female athymic nude mice inoculated with OPM-2 luciferase cells were orally administered with both compounds.
6 shows superior in vivo efficacy of Example 13 and Example 14 relative to Reference Compound 1 in tumor PD models. Female athymic nude mice inoculated with OPM-2 luciferase cells were orally administered with both compounds.
FIG. 7 shows the superior in vivo efficacy of Example 18 compared to Reference Compound 1 in tumor PD models. Female athymic nude mice inoculated with OPM-2 luciferase cells were orally administered with both compounds.
8 shows the in vivo efficacy of Example 1 in an OPM-2 xenograft efficacy model. Example 1 was orally administered to female athymic nude mice inoculated with OPM-2 luciferase cells.
9 shows the in vivo efficacy of Example 4 in an OPM-2 xenograft efficacy model. Example 1 was orally administered to female athymic nude mice inoculated with OPM-2 luciferase cells.
10 shows the in vivo efficacy of Example 10 in an OPM-2 xenograft efficacy model. Example 1 was orally administered to female athymic nude mice inoculated with OPM-2 luciferase cells.
11 shows the in vivo efficacy of Example 11 in an OPM-2 xenograft efficacy model. Example 1 was orally administered to female athymic nude mice inoculated with OPM-2 luciferase cells.
12 shows the in vivo efficacy of Example 13 in an OPM-2 xenograft efficacy model. Example 1 was orally administered to female athymic nude mice inoculated with OPM-2 luciferase cells.
FIG. 13 shows the in vivo efficacy of Example 18 in an OPM-2 xenograft efficacy model. Example 1 was orally administered to female athymic nude mice inoculated with OPM-2 luciferase cells.

The symbol "-" denotes a covalent bond and may also be used in radical groups to indicate the point of attachment to another group. In chemical structures, the symbol "-" is usually used to denote a methyl group in a molecule.

및

)으로 도시된 하나 이상의 입체중심을 포함하는 화학 구조는 화학 구조에 존재하는 입체중심(들)의 절대 입체화학을 나타내도록 의미를 갖는다. 본원에서 사용되는 바와 같이, 단순한 선에 의해 기호화된 결합은 입체-선호도(stereo-preference)를 나타내지 않는다. 달리 반대로 표시되지 않는 한, 절대적 또는 상대적 입체화학이 표시되지 않고 본원에 도시된 하나 이상의 입체 중심을 포함하는 화학 구조는 화합물의 모든 가능한 입체이성질체 형태(예를 들어, 부분입체이성질체, 거울상이성질체) 및 이의 혼합물을 포함한다. 하나의 굵은 선 또는 파선, 및 적어도 하나의 추가적인 단순한 선을 갖는 구조는 모든 가능한 부분입체이성질체의 단일 거울상이성질체 시리즈를 포함한다.As used herein, dashed and thick line combinations (ie,

And

A chemical structure comprising one or more stereocenters, shown as), is meant to represent the absolute stereochemistry of the stereocenter (s) present in the chemical structure. As used herein, bonds symbolized by simple lines do not exhibit stereo-preferences. Unless otherwise indicated to the contrary, chemical structures comprising one or more stereocenters as shown herein, without absolute or relative stereochemistry, are shown that include all possible stereoisomeric forms of the compounds (eg, diastereomers, enantiomers) and Mixtures thereof. Structures with one bold or dashed line, and at least one additional simple line, comprise a single enantiomeric series of all possible diastereomers.

As used herein, the term “about” is meant to describe a change due to experimental error. All measurement values reported herein are understood to be modified by the term “about” whether or not the term is expressly used unless explicitly stated otherwise. As used herein, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise.

The term "alkyl" refers to a straight chain or branched chain hydrocarbon. Representative examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, secondary-butyl, pentyl and hexyl. Typical alkyl groups are alkyl groups having from 1 to 8 carbon atoms, the group is typically C ₁ - it is represented as an _8-alkyl.

As used herein, the term “compound” is meant to include all stereoisomers, geometric isomers, tautomers and isotopes of the depicted structure. Compounds herein, identified by name or structure as one particular tautomeric form, are intended to include other tautomeric forms unless otherwise specified.

All compounds and their pharmaceutically acceptable salts can be found with other materials such as water and solvents (eg hydrates and solvates).

The term “cycloalkyl” means a cyclic, non-aromatic hydrocarbon. Representative examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Cycloalkyl groups can include one or more double bonds. Representative examples of cycloalkyl groups containing double bonds include cyclopentenyl, cyclohexenyl, cyclohexadienyl and cyclobutanedienyl. Typical cycloalkyl groups are C _3-8 cycloalkyl groups.

As used herein, the term “excipient” refers to any pharmaceutically acceptable additive, carrier, diluent, adjuvant or other ingredient other than an active pharmaceutical ingredient (API), which It is generally included for formulation and / or for administration to a patient. See Handbook of Pharmaceutical Excipients, 5 ^th Edition, RC Rowe, PJ Sheskey, and SC Owen, editors, Pharmaceutical Press, 2005, Hardback, 928, 0853696187.

The terms “for example” and “such as” and their grammatical synonyms are understood to be followed by the phrase “and without limitation,” unless expressly stated otherwise. do.

The term "halogen" or "halo" means F, Cl, Br or I.

The term “patient” refers to a subject including animals such as dogs, cats, cattle, horses, sheep, and humans. Particular patients are mammals. The term "patient" includes males and females.

The term “patient in need” refers to a patient having or at risk of having one or more diseases or conditions involving Mcl-1 protein, such as cancer. Identifying a patient in need may be at the discretion of the subject or health care professional and may be subjective (eg finding) or objective (eg being measurable by a test or diagnostic method).

As used herein, the phrases “parenteral administration” and “administered parenterally” refer to modes of administration other than enteral and topical administration, usually by injection, and are intravenous. Intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardial, intradermal, intraperitoneal, bronchial include, but are not limited to, transcheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, and intrasternal injections and infusions, It is not limited to these.

Compositions suitable for parenteral injection may include physiologically acceptable sterile aqueous solutions or non-aqueous solutions, dispersions, suspensions, or emulsions, and sterile powders for reconstitution into sterile injections or dispersions. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents, or vehicles include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (eg olive oil), and injectable organic esters such as Ethyl oleate. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

The term “pharmaceutically acceptable” refers herein to corresponding ligands, substances, compositions and / or dosage forms that correspond to a rational benefit / risk ratio and are suitable for administration to a patient within the scope of sound medical judgment. Used in

The phrase “pharmaceutically acceptable carrier” as used herein refers to a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. it means. As used herein, the term “pharmaceutically acceptable carrier” refers to pharmaceutically administrable buffers, sterile water for injection, solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. Include. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not harmful to the patient. Some examples of materials that can serve as pharmaceutically acceptable carriers include: (1) sugars such as lactose, glucose and sucrose; (2) starches such as corn starch, potato starch, and substituted or unsubstituted β-cyclodextrins; (3) cellulose, and derivatives thereof such as carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; (4) powder tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients such as cocoa butter and suppository waxes; (9) oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols, such as propylene glycol; (11) polyols such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; And (21) other nontoxic compatible materials used in pharmaceutical formulations. In certain claims, the pharmaceutical compositions provided herein are nonpyrogenic and do not induce significant temperature rises when administered to a patient.

The term “pharmaceutically acceptable salt” refers to the relatively nontoxic, inorganic and organic acid addition salts of the compounds provided herein. These salts can be prepared in situ during the final isolation and purification of the compounds provided herein, or by reacting the compounds in free base form separately with the appropriate organic or inorganic acid and isolating the salts so formed. . Representative salts are hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citric acid Salts, maleates, fumarates, succinates, tartarates, naphthylates, mesylates, glucoheptonates, lactobionates, laurylsulfonates, amino acid salts and the like. (See, eg, Berge et al. (1977) “Pharmaceutical Salts”, J. Pharm . Sci. 66: 1-19).

As used herein, the terms “systemic administration”, “administered systemically”, “peripheral administration” and “administered peripherally” refer to ligands, drugs or By means of routes not directly administered into the central nervous system, eg, subcutaneous administration, such that other substances enter the patient's system and undergo metabolism and other similar processes.

The term “therapeutically effective amount” means an amount of a compound that alleviates, attenuates, or eliminates one or more symptoms of a particular disease or condition, or prevents or delays the development of one or more symptoms of a particular disease or condition. .

The terms “treating”, “treat” or “treatment” and the like include prophylactic (eg prophylactic) and palliative treatments.

Embodiment A

The embodiments listed below are presented in numbered form for convenience and again for ease of reference and clarity when referring to a number of embodiments.

In a first embodiment, the present invention provides a compound of formula I '

Formula I ';

Stereoisomers thereof, pharmaceutically acceptable salts thereof, or pharmaceutically acceptable salts of stereoisomers thereof,

In the formula,

Z is C or N;

Q is O or S;

W is CR ^WA R ^WB or ^C═O ;

R ^WA and R ^WB are independently selected from H, C _1-3 alkyl, halo, -OH, or -OC _1-3 alkyl;

로 표시되는 b는 시스 또는 트랜스일 수 있는 단일 또는 이중 화학 결합이고; symbol

B is a single or double chemical bond which may be cis or trans;

R ¹ is H, halo, C _1-6 alkylhalo, C _1-6 alkyl,-(CH ₂ CH ₂ O) _n R ^a , -SO ₂ R ^a , -C (= O) R ^a , -C Independently selected from (═O) OR ^a , or —C (═O) NR ^a R ^b ;

R ² is H, halo, -C _1-6 haloalkyl, -C _1-6 alkyl, -OC _1-6 alkyl, -C _2-6 alkenyl, -C _1-6 alkyl-OC _1-6 alkyl, -(CH ₂ CH ₂ O) _n R ^a , -SO ₂ R ^a , -C (= 0) R ^a , -C (= 0) OR ^a , -OC (= 0) R ^a , or -C (= O) NR ^a R ^b ;

R ³ is H, —C _1-6 alkylhalo, —C _1-6 alkyl, —C _2-6 alkenyl, — (CH ₂ CH ₂ O) _n R ^a , —C (═O) R ^a , Independently from -C (= 0) OR ^a , or -C (= 0) NR ^a R ^b ;

R ⁴ , R ⁵ , R ⁶ , R ⁷ , and R ⁸ are each H, halo, -C _1-6 haloalkyl, -C _1-6 alkyl, -OC _1-6 alkyl, -C _2-6 alkenyl , -C _1-6 alkyl-OC _1-6 alkyl,-(CH ₂ CH ₂ O) _n R ^a , -SO ₂ R ^a , -C (= O) R ^a, -C (= O) OR ^a , -OC (= 0) R ^a , -C (= 0) NR ^a R ^b , 6- to 12-membered aryl or heteroaryl, 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, 3- Independently selected from membered to 12-membered cycloalkenyl, 3-membered to 12-membered monocyclic or bicyclic cycloalkyl, or 3-membered to 12-membered monocyclic or bicyclic heterocycloalkyl group, heteroaryl, spiroheterocycloalkyl and Heterocycloalkyl groups have 1, 2, 3 or 4 heteroatoms independently selected from O, N or S, and cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkyl groups can include C═O groups And further spiroheterocycloalkyl and heterocycloalkyl It may comprise a S = O or SO _2, and;

Alternatively, R ³ and R ⁴ together with the atoms to which they are attached form a 5-membered to 12-membered ring, wherein in addition to the S and N atoms present in the ring, a heteroatom selected from N, O or S atoms is optionally To form a containing ring, the ring may optionally contain at least one double bond, and the ring may be substituted with 0, 1, 2, or 3 R ^3A substituents;

R ^3A is H, halo, -OH, C _1-6 haloalkyl, C _1-6 alkyl, OC _1-6 alkyl, C _2-6 alkenyl, -C _1-6 alkyl-OC _1-6 alkyl,- (CH ₂ CH ₂ O) _n R ^a , -SO ₂ R ^a , -C (= 0) R ^a , -C (= 0) OR ^a , -OC (= 0) R ^a , or -C (= 0) ) NR ^a R ^b independently;

Each of R ^4A , R ^5A , R ^6A , R ^7A , and R ^8A is independently selected from H, OH, halo, —C _1-6 alkyl;

R ^7A and R ^8A are absent when b is a double chemical bond;

R ⁹ is H, -C _1-6 haloalkyl, -C _1-6 alkyl, -C _2-6 alkenyl, -C _2-6 alkynyl,-(CH ₂ CH ₂ O) _n R ^a , -C (═O) R ^a , —C (═O) OR ^a , —C (═O) NR ^a R ^b , —C _1-6 alkyl-OC _1-6 alkyl, 6- to 12-membered aryl or hetero Aryl, 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, 3- to 12-membered cycloalkenyl, 3- to 12-membered monocyclic or bicyclic cycloalkyl, or 3- to 12-membered Independently selected from monocyclic or bicyclic heterocycloalkyl groups, heteroaryl, spiroheterocycloalkyl or heterocycloalkyl groups have 1, 2, 3 or 4 heteroatoms independently selected from O, N or S, cycloalkyl, spiro Cycloalkyl, spiroheterocycloalkyl, and heterocycloalkyl groups may comprise C═O groups, and further, spirohterocycloalkyl and heterocycloalkyl groups may comprise S═O or SO ₂ ;

R ^9A is H, C _1-6 haloalkyl, C _1-6 alkyl, -C _2-6 alkenyl, -C _2-6 alkynyl,-(CH ₂ CH ₂ O) _n R ^a , -SO ₂ R ^a , -C (= 0) R ^a , -C (= 0) OR ^a , -C (= 0) NR ^a R ^b , -NR ^a R ^b , -N = N = N, -C _1-6 alkyl -OC _1-6 alkyl, 6- to 12-membered aryl, 6- to 12-membered heteroaryl, 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, 3- to 12-membered cyclo Alkenyl, 3-membered to 12-membered monocyclic or bicyclic cycloalkyl, or 3-membered to 12-membered monocyclic or bicyclic heterocycloalkyl group, and heteroaryl, spirohterocycloalkyl and heterocycloalkyl group are O, Cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkyl groups having 1, 2, 3, or 4 heteroatoms independently selected from N or S, may comprise a C═O group, and further spiro Heterocycloalkyl and heterocycloalkyl groups are S═O or SO May comprise ₂ ;

The aryl, heteroaryl, cycloalkyl, heterocycloalkyl, spirocycloalkyl and ^{spirterocycloalkyl} groups of the R ^9A substituent are unsubstituted or substituted with OH, halo, -NR ^c R ^d , -C _1-6 alkyl, -C ₂ -C ₆ alkenyl, -C ₂ -C ₆ alkynyl, -OC _1-6 alkyl, -C _1-6 alkyl-OH, -C _1-6 alkyl-OC _1-6 alkyl, C _1-6 haloalkyl,- O-haloC _1-6 alkyl, -SO ₂ R ^c , -CN, -C (= 0) NR ^c R ^d , -C (= 0) R ^c , -OC (= 0) R ^a , -C ( = O) OR ^c , 6- to 12-membered aryl, 6- to 12-membered heteroaryl, 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, 3- to 12-membered cycloal May be substituted with 1, 2, 3 or 4 R ¹⁰ substituents independently selected from kenyl, 3- to 12-membered monocyclic or bicyclic cycloalkyl, or 3- to 12-membered monocyclic or bicyclic heterocycloalkyl groups, Heteroaryl, spiroheterocycloalkyl, and heterocycloalkyl groups are 0, independently selected from O, N or S, Having 1, 2, 3 or 4 heteroatoms, the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkyl groups can comprise C═O groups, and further the spiroheterocycloalkyl and heterocycloalkyl groups May comprise S═O or SO ₂ ;

Alternatively, R ⁹ and R ^9A form a 3-membered to 12-membered monocyclic or bicyclic ring together with Q, W and C to which W and Q bond, a hetero group other than Q selected from N, O or S A ring optionally containing atoms may be formed, the ring may contain a double bond, the ring may optionally include a C═O group, and further the ring may be substituted by 1, 2, or 3 R ¹¹ substituents May be optionally substituted;

R ¹¹ is OH, halo, -NR ^c R ^d , -C _1-6 alkyl, -OC _1-6 alkyl, -C _1-6 alkyl-OH, -C _1-6 alkyl-OC _1-6 alkyl, C _1-6 haloalkyl, -O-haloC _1-6 alkyl, -SO ₂ R ^c , -CN, -C (= 0) NR ^c R ^d , -C (= 0) R ^c , -OC (= 0 ) R ^a , -C (= 0) OR ^c , 6- to 12-membered aryl or heteroaryl, 6- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, 3- to 12-membered cycloal Independently selected from kenyl, 3- to 12-membered monocyclic or bicyclic cycloalkyl, or 3- to 12-membered monocyclic or bicyclic heterocycloalkyl groups, heteroaryl, spiroheterocycloalkyl, and heterocycloalkyl groups being O, Cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkyl groups having 1, 2, 3 or 4 heteroatoms independently selected from N or S, may comprise a C═O group, and further spirohetero Cycloalkyl and heterocycloalkyl groups are S = O or May include SO ₂ ;

R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ^4A , R ^5A , R ^6A , R ^7A , R ^8A and R ^9A -C _1-6 alkyl of any of the substituents is unsubstituted or OH, -OC _1-6 alkyl, -C _1-6 alkyl-OC _1-6 alkyl, halo, -O-haloC _1-6 alkyl,- CN, -NR ^a R ^b ,-(NR ^a R ^b R ^c ) _n , -SO ₂ R ^a ,-(CH ₂ CH ₂ O) _n CH ₃ , (= O), -C (= O),- C (= O) R ^a , -OC (= O) R ^a , -C (= O) OR ^a , -C (= O) NR ^a R ^b , -O-SiR ^a R ^b R ^c , -O- (3- to 12-membered heterocycloalkyl), phenyl, 6- to 12-membered aryl or heteroaryl, 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, 3- to 12-membered Substituted by 1, 2 or 3 R ¹² substituents independently selected from cycloalkenyl, 3- to 12-membered monocyclic or bicyclic cycloalkyl, or 3- to 12-membered monocyclic or bicyclic heterocycloalkyl groups, and hetero Aryl, spiroheterocycloalkyl and heterocycloalkyl groups are poisons from O, N or S The cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkyl groups having one, two, three or four heteroatoms selected, may comprise a C═O group, and further, spiroheterocycloalkyl and hetero Cycloalkyl groups may include S═O or SO ₂ ;

R ² , R ⁴ , R ⁵ , The aryl, heteroaryl, cycloalkyl, heterocycloalkyl, spirocycloalkyl and spiroheterocycloalkyl groups of any one of the R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ and R ¹² substituents are unsubstituted or OH , Halo, -C _1-6 alkyl, -OC _1-6 alkyl, -C _1-6 alkyl-OH, -C _1-6 alkyl-OC _1-6 alkyl, C _1-6 haloalkyl, -O-halo C _1-6 alkyl, —SO ₂ R ^c , —NR ^c R ^d , —CN, —C (═O) NR ^c R ^d , —C (═O) R ^c , —OC (═O) R ^a , -C (= 0) OR ^c , -B (OH) ₂ , 6- to 12-membered aryl or heteroaryl, 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, 3- to 12- To be substituted with 1, 2, 3 or 4 R ¹³ substituents independently selected from membered cycloalkenyl, 3-membered to 12-membered monocyclic or bicyclic cycloalkyl, or 3-membered to 12-membered monocyclic or bicyclic heterocycloalkyl group Wherein the heteroaryl, spiroheterocycloalkyl, and heterocycloalkyl groups are independently from O, N, or S With 1, 2, 3 or 4 heteroatoms selected, the cycloalkyl, spirocycloalkyl, spirocyclocycloalkyl, and heterocycloalkyl groups can comprise C═O groups, further spiroheterocycloalkyl and heterocycloalkyl groups May comprise S═O or SO ₂ ;

Each R ^a , R ^b , R ^c , and R ^d is independently H, OH, -C _1-6 alkyl, -C _1-6 alkenyl, -C _2-6 alkynyl, -C _1-6 alkyl -NR ¹⁴ R ¹⁴ , NR ¹⁴ R ¹⁴ , -SO ₂ R ¹⁴ ,-(CH ₂ CH ₂ O) _n CH ₃ , (= O), -C (= O) R ¹⁴ , -OC (= O) R ¹⁴ , -C (= 0) OR ¹⁴ , -C (= 0) NR ¹⁴ R ¹⁴ , C _1-6 haloalkyl, -O-haloC _1-6 alkyl, -C _1-6 alkyl-OC _1-6 Alkyl, -C _1-6 alkyl-OH, benzyl, phenyl, -C _1-6 alkyl-3-membered to 12-membered heterocycloalkyl, 6-membered to 12-membered aryl or heteroaryl, 5-membered to 12 -Membered spirocycloalkyl or spiroheterocycloalkyl, 3- to 12-membered cycloalkenyl, 3- to 12-membered monocyclic or bicyclic cycloalkyl, or 3- to 12-membered monocyclic or bicyclic heterocycloalkyl group , heteroaryl, spiro-heterocycloalkyl, and heterocycloalkyl group and a -C _1-6 alkyl- is a heterocycloalkyl group of the heterocycloalkyl group is O, N or S 1, 2, 3 or 4 heteroatoms independently selected from And, cycloalkyl, spiro cycloalkyl, spiro-heterocycloalkyl, heterocycloalkyl, and -C _1-6 alkyl-heterocycloalkyl group in heterocycloalkyl group may include a group C = O, spiro-heterocycloalkyl, and additionally Heterocycloalkyl groups may include S═O or SO ₂ ;

Heterocycloalkyl groups of alkyl, aryl, heteroaryl, spirocycloalkyl, spiroheterocycloalkyl, cycloalkyl, heterocycloalkyl and -C _1-6 alkyl-heterocycloalkyl groups of R ^a , R ^b , R ^c , and R ^d Is unsubstituted or substituted with H, OH, -N = N = N, halo, -C _1-6 alkyl, -OC _1-6 alkyl, C _1-6 haloalkyl, -O-haloC _1-6 alkyl, phenyl, 1, 2, 3, or 4 independently selected from tolyl, -C (O) C _1-6 alkyl, -C (O) OCH ₃ , SO ₂ -phenyl, or -SO ₂ -N (CH ₃ ) ₂ May be substituted with a R ¹⁴ substituent;

n is independently at each occurrence an integer of 1, 2, 3 or 4.

2. Another embodiment of the present invention includes a compound of embodiment 1 or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of stereoisomer thereof, wherein the compound of formula I ' I'a

Formula I'a

Has

3. The compound of any one of embodiments 1 or 2, wherein b is a double bond, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of stereoisomer thereof.

4. The compound according to any one of embodiments 1 or 2, wherein b is a single bond, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of stereoisomer thereof.

5. The compound of any of embodiments 1-4, wherein Z is C, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of stereoisomer thereof.

6. The compound of any one of embodiments 1 to 4, wherein Z is N, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of stereoisomer thereof.

7. The compound of any one of embodiments 1 to 6, wherein Q is O, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of stereoisomer thereof.

8. The compound of any one of embodiments 1 to 6 wherein Q is S, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of stereoisomer thereof.

9. The compound according to any one of embodiments 1 to 8, wherein W is C═O, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of stereoisomer thereof.

10. The compound according to any one of embodiments 1 to 8, wherein W is CR ^WA R ^WB , or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of stereoisomer thereof.

11. The pharmaceutically acceptable compound of any one of embodiments 1 to 8 and 10, wherein R ^WA and R ^WB are both H, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof. salt.

12. The compound of any of embodiments 1-11, wherein R ¹ is a halo compound, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of stereoisomer thereof.

13. The compound of any one of embodiments 1 to 12, wherein R ¹ is Cl, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of stereoisomer thereof.

14. The compound of any one of embodiments 1 to 13, wherein R ² is H, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of stereoisomer thereof.

15. The pharmaceutically acceptable compound of any one of embodiments 1 to 14, wherein R ³ is H or -C _1-6 alkyl, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof. salt.

16. The compound of any one of embodiments 1-15, wherein R ³ is -CH ₃ , or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of stereoisomer thereof.

17. The compound of any of embodiments 1-15, wherein R ³ is H, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of stereoisomer thereof.

18. The compound of any of embodiments 1 to 17, wherein R ⁴ is H, -C _1-6 alkyl, -C _1-6 alkylhalo, -C _1-6 alkyl-OC _1-6 alkyl, or-( CH ₂ CH ₂ O) _n independently selected from R ^a , -C _1-6 alkyl is unsubstituted or -OH, (= O), phenyl, -O-SiR ^a R ^b R ^c , -NR ^a R ^b , substituted with a 3-membered to 12-membered cycloalkyl, or O, N or S is selected independently from 1, 2, 3, or 4 has the heteroatoms is 3-membered to 12-membered monocyclic or bicyclic heterocycloalkyl To a compound, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof.

19. The compound of any one of embodiments 1 to 18, wherein R ⁴ is H, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of stereoisomer thereof.

20. The compound of any of embodiments 1-18, wherein R ⁴ is —C _1-6 alkyl, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of stereoisomer thereof.

21. The compound of any of embodiments 1-18 or 20, wherein R ⁴ is -CH ₃ , or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of stereoisomer thereof.

22. The compound of any of embodiments 1-18, wherein R ⁴ is —C _1-6 alkyl-OC _1-6 alkyl, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof Scholarly acceptable salts.

23. The pharmaceutically acceptable compound of any one of embodiments 1 to 18 or 22, wherein R ⁴ is -CH ₂ CH ₂ OCH ₃ , or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof. Possible salts.

24. The pharmaceutically acceptable compound of any one of embodiments 1 to 18, wherein R ⁴ is -C _1-6 alkyl-OH, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof. salt.

25. The pharmaceutically acceptable compound of any one of embodiments 1 to 18, wherein R ⁴ is -C _1-6 alkyl = O, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof. salt.

26. The pharmaceutically acceptable compound of any one of embodiments 1 to 18, wherein R ⁴ is -C _1-6 alkyl-phenyl, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof. salt.

27. The compound of any one of embodiments 1 to 18, wherein R ⁴ is —C _1-6 alkyl-O—SiR ^a R ^b R ^c , or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a steric thereof Pharmaceutically acceptable salts of the isomers.

28. The pharmaceutical of any of embodiments 1-18, wherein R ⁴ is —C _1-6 alkyl-NR ^a R ^b , or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof. Acceptable salts.

29. The compound of any of embodiments 1-18, wherein R ⁴ is —C _1-6 alkyl-C ₃ -C ₆ cycloalkyl, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof Pharmaceutically acceptable salts of.

30. -C _1-6 alkyl-C ₃ -C ₁₀ according to any one of embodiments 1 to 18, wherein R ⁴ has 1, 2, 3, or 4 heteroatoms independently selected from O, N or S A compound that is heterocycloalkyl, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof.

인 화합물, 또는 이의 입체이성질체, 이의 약제학적으로 허용 가능한 염, 또는 이의 입체이성질체의 약제학적으로 허용 가능한 염.31. The compound of any of embodiments 1 to 18, wherein R ⁴ is

Phosphorus compounds, or stereoisomers thereof, pharmaceutically acceptable salts thereof, or pharmaceutically acceptable salts of stereoisomers thereof.

인 화합물, 또는 이의 입체이성질체, 이의 약제학적으로 허용 가능한 염, 또는 이의 입체이성질체의 약제학적으로 허용 가능한 염.32. The compound of any of embodiments 1-18, wherein R ⁴ is

Phosphorus compounds, or stereoisomers thereof, pharmaceutically acceptable salts thereof, or pharmaceutically acceptable salts of stereoisomers thereof.

33. The compound of any of embodiments 1-18, wherein R ⁴ is —CH ₃ , —CH ₂ CH ₂ OCH ₃ ,

로부터 독립적으로 선택되는 화합물, 또는 이의 입체이성질체, 이의 약제학적으로 허용 가능한 염, 또는 이의 입체이성질체의 약제학적으로 허용 가능한 염.

A compound selected independently from, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof.

34. The compound of any of embodiments 1-14, wherein R ³ and R ⁴ together with the atoms to which they are attached form a 5- to 12-membered ring, in addition to the S and N atoms present in the ring, N, O Or a ring optionally containing a heteroatom selected from S, the ring may optionally contain at least one double bond, and further the ring is substituted with 0, 1, 2, or 3 R ^3A substituents A compound, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof.

35. The compound of any of embodiments 1 to 14 or 34, wherein R ³ and R ⁴ together with the atoms to which they are attached form a compound, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof Pharmaceutically acceptable salts of:

.

.

36. The pharmaceutically acceptable compound of any one of embodiments 1 to 35, wherein R ⁵ is H or —C _1-6 alkyl, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof. salt.

37. The compound of any of embodiments 1 to 36, wherein R ⁵ is —CH ₃ , or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of stereoisomer thereof.

38. The compound of any one of embodiments 1 to 36, wherein R ⁵ is H, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of stereoisomer thereof.

39. The pharmaceutically acceptable compound of any one of embodiments 1 to 38, wherein R ⁶ is H or -C _1-6 alkyl, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof. salt.

40. The compound of any of embodiments 1-38, wherein R ⁶ is -CH ₃ , or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of stereoisomer thereof.

41. The compound of any of embodiments 1-38, wherein R ⁶ is H, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of stereoisomer thereof.

42. The compound of any of embodiments 1-41, wherein each of R ^4A , R ^5A , R ^6A , R ^7A and R ^8A is independently selected from H, OH, halo, or —C _1-6 alkyl, or Stereoisomers thereof, pharmaceutically acceptable salts thereof, or pharmaceutically acceptable salts of stereoisomers thereof.

43. The compound of embodiment 42, wherein R ^4A , R ^5A , R ^6A , R ^7A and R ^8A are each H, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of the stereoisomer thereof. Possible salts.

44. The pharmaceutical composition of any one of embodiments 1, 2 or 4 to 43, wherein R ^7A and R ^8A are both H, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof Acceptable salts.

45. The compound of any of embodiments 1-44, wherein R ⁷ and R ⁸ are both H, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of stereoisomer thereof.

46. The compound of any of embodiments 1 to 45, wherein R ⁹ is H, -C _1-6 alkyl, -C _2-6 alkenyl, or -C _1-6 alkyl-OC _1-6 alkyl or -C ₁ A compound independently selected from _-6 haloalkyl, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof.

47. The compound of any of embodiments 1-46, wherein R ⁹ is H, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of stereoisomer thereof.

48. The compound of any of embodiments 1-46, wherein R ⁹ is -CH ₃ , or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of stereoisomer thereof.

49. The compound of any of embodiments 1-46, wherein R ⁹ is -CH ₂ CH ₃ , or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of stereoisomer thereof.

50. The pharmaceutically acceptable of any one of embodiments 1 to 46, wherein R ⁹ is -CH ₂ CH (CH ₃ ) ₂ , or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof. Possible salts.

51. The compound of any of embodiments 1-46, wherein R ⁹ is -CH ₂ CH ₂ OCH ₃ , or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of stereoisomer thereof. .

52. The compound of any of embodiments 1-46, wherein R ⁹ is -CF ₃ , or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of stereoisomer thereof.

53. The compound of any of embodiments 1 to 52, wherein R ^9A is H, C _1-6 haloalkyl, C _1-6 alkyl, -C _2-6 alkenyl,-(CH ₂ CH ₂ O) _n R ^a , -SO ₂ R ^a , -C (= O) R ^a , -C (= O) OR ^a , -C (= O) NR ^a R ^b , -NR ^a R ^b , -N = N = N,- C _1-6 alkyl-OC _1-6 alkyl, 6- to 12-membered aryl, 6- to 12-membered heteroaryl, 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, 3-membered To a 12-membered cycloalkenyl, a 3-membered to 12-membered monocyclic or bicyclic cycloalkyl, or a 3-membered to 12-membered monocyclic or bicyclic heterocycloalkyl group, and a heteroaryl, spiroheterocycloalkyl and heterocycloalkyl group Has 1, 2, 3, or 4 heteroatoms independently selected from O, N or S, and the cycloalkyl, spirocycloalkyl, spirohterocycloalkyl, and heterocycloalkyl groups may comprise a C═O group, Additionally spiroheterocycloalkyl and heterocycloal The kill group may comprise S═O or SO ₂ , or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of stereoisomer thereof.

54. The compound of any of embodiments 1-53, wherein R ^9A is —C _1-6 alkyl, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of stereoisomer thereof.

55. The compound of any of embodiments 1-53, wherein R ^9A is -C (= 0) R ^a , or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of stereoisomer thereof. salt.

56. The compound of any of embodiments 1 to 53, wherein R ^9A is a 3- to 12-membered monocyclic or bicyclic heterocycloalkyl group, wherein the heterocycloalkyl group is independently selected from O, N or S; Or a compound having four heteroatoms, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of its stereoisomer.

57. The compound of any of embodiments 1 to 53, wherein R ^9A is a 3- to 12-membered monocyclic heterocycloalkyl group, and the heterocycloalkyl group is 1, 2, 3, or 4 heteros independently selected from O or N A compound having an atom, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof.

58. The compound of any of embodiments 1-53, 56 or 57, wherein the 3- to 12-membered monocyclic heterocycloalkyl R ^9A group is unsubstituted or substituted with OH, halo, -NR ^c R ^d , -C _1-6 alkyl , -C ₂ -C ₆ alkenyl, -C ₂ -C ₆ alkynyl, -OC _1-6 alkyl, -C _1-6 alkyl-OH, -C _1-6 alkyl-OC _1-6 alkyl, C _{1 -6} haloalkyl, -O-haloC _1-6 alkyl, -SO ₂ R ^c , -CN, -C (= 0) NR ^c R ^d , -C (= 0) R ^c , -OC (= 0) R ^a , -C (= 0) OR ^c , 6- to 12-membered aryl, 6- to 12-membered heteroaryl, 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, 3-membered 1, 2, 3 or 4 R ¹⁰ substituents independently selected from to 12-membered cycloalkenyl, 3-membered to 12-membered monocyclic or bicyclic cycloalkyl, or 3-membered to 12-membered monocyclic or bicyclic heterocycloalkyl group And a heteroaryl, spiroheterocycloalkyl, or heterocycloalkyl group can be substituted with 1, 2, 3 or 4 independently selected from O, N or S Wherein the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkyl groups may comprise C═O groups, and further, the spiroheterocycloalkyl and heterocycloalkyl groups may represent S═O or SO ₂ Compounds that may include, or stereoisomers thereof, pharmaceutically acceptable salts thereof, or pharmaceutically acceptable salts of stereoisomers thereof.

59. The compound of any of embodiments 1 to 58, wherein the 1, 2, 3 or 4 R ¹⁰ substituents are independently selected from -C _1-6 alkyl or a 3- to 12-membered monocyclic heterocycloalkyl group, and hetero Cycloalkyl groups are compounds having one, two, three, or four heteroatoms independently selected from O, N, or S, or stereoisomers thereof, pharmaceutically acceptable salts thereof, or pharmaceutically acceptable compounds of stereoisomers thereof salt.

60. The compound of any of embodiments 1-59, wherein R ¹⁰ is —C _1-6 alkyl, or a stereoisomer, pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of stereoisomer thereof.

61. The compound of any of embodiments 1 to 59, wherein R ¹⁰ is a 3- to 12-membered monocyclic heterocycloalkyl group, and the heterocycloalkyl group is 1, 2, 3, or 4 independently selected from O, N or S Compounds having 2 heteroatoms, or stereoisomers thereof, pharmaceutically acceptable salts thereof, or pharmaceutically acceptable salts of stereoisomers thereof.

62. The compound of any of embodiments 1 to 53, wherein R ^9A is a 5- to 12-membered bicyclic heterocycloalkyl group, and the heterocycloalkyl group is 1, 2, 3, or 4 heteros independently selected from O or N A compound having an atom, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof.

63. The compound of any of embodiments 1 to 52, wherein R ^9A is -N = N = N,

, 또는

으로부터 독립적으로 선택되는 화합물, 또는 이의 입체이성질체, 이의 약제학적으로 허용 가능한 염, 또는 이의 입체이성질체의 약제학적으로 허용 가능한 염.

, or

A compound selected independently from, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof.

64. The compound of any of embodiments 1 to 45, wherein R ⁹ and R ^{9A together} with Q, W and C to which W and Q bond form a 3- to 12-membered monocyclic or bicyclic ring, wherein N, May form a ring optionally containing a heteroatom other than Q selected from O or S, the ring may comprise a double bond, the ring may optionally comprise a C═O group, and further the ring may be 1, 2, Or a compound optionally substituted by three R ¹¹ substituents, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of its stereoisomer.

65. The compound of any one of embodiments 1 to 45 and 64, wherein R ⁹ and R ^9A together with the atoms to which they are attached form a compound selected from: or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or Pharmaceutically acceptable salts of its stereoisomers:

인 화합물, 또는 이의 입체이성질체, 이의 약제학적으로 허용 가능한 염, 또는 이의 입체이성질체의 약제학적으로 허용 가능한 염.66. The compound of any of embodiments 1 to 9, 12 to 52, or 64, wherein R is ^9A when W is ^C═O .

Phosphorus compounds, or stereoisomers thereof, pharmaceutically acceptable salts thereof, or pharmaceutically acceptable salts of stereoisomers thereof.

67. The compound of any of embodiments 1-11 or 14-66, wherein R ¹ is H, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of stereoisomer thereof.

68. Another embodiment of the present invention includes a compound of embodiment 1 or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of stereoisomer thereof, wherein the compound of Formula I ' II '

[Formula II ']

Has

69. Another embodiment of the present invention includes a compound of any one of embodiments 1, 2 or 68 or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of stereoisomer thereof, Compound of Formula (I ') is represented by Formula (II'a)

Formula II'a;

Has

70. The compound of any of embodiments 1, 2, 68 or 69, wherein R ⁴ is H, -C _1-6 alkyl, -C _1-6 alkylhalo, -C _1-6 alkyl-OC _1-6 alkyl , Or-(CH ₂ CH ₂ O) _n R ^a independently, -C _1-6 alkyl is unsubstituted or -OH, (= O), phenyl, -O-SiR ^a R ^b R ^c ,- NR ^a R ^b , 3- to 12-membered cycloalkyl, or 3- to 12-membered monocyclic or bicyclic heterocyclo having 1, 2, 3, or 4 heteroatoms independently selected from O, N or S Compounds substituted with alkyl, or stereoisomers thereof, pharmaceutically acceptable salts thereof, or pharmaceutically acceptable salts of stereoisomers thereof.

71. The pharmaceutical composition of any one of embodiments 1, 2, 68 to 69, or 70, wherein R ⁴ is -CH ₃ , or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof. Acceptable salts.

72. The compound of any one of embodiments 1, 2, 68 to 69, or 70, wherein R ⁴ is —CH ₂ CH ₂ OCH ₃ , or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof. Pharmaceutically acceptable salts of.

73. The compound of any one of embodiments 1, 2, 68 to 71 or 72, wherein R ⁵ is H or -C _1-6 alkyl, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof Pharmaceutically acceptable salts of.

74. The pharmaceutically acceptable compound of any one of embodiments 1, 2, 68 to 71 or 72, wherein R ⁵ is -CH ₃ , or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof. Possible salts.

75. The compound of any one of embodiments 1, 2, 68 to 71 or 72, wherein R ⁵ is H, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of stereoisomer thereof. .

76. The compound of any one of embodiments 1, 2, 68 to 74 or 75, wherein R ⁶ is H or -C _1-6 alkyl, or a stereoisomer, pharmaceutically acceptable salt thereof, or stereoisomer thereof Pharmaceutically acceptable salts of.

77. The pharmaceutically acceptable compound of any one of embodiments 1, 2, 68 to 75 or 76, wherein R ⁶ is -CH ₃ , or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof. Possible salts.

78. The compound of any one of embodiments 1, 2, 68 to 75 or 76, wherein R ⁶ is H, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of stereoisomer thereof. .

79. The compound of any of embodiments 1, 2, 68 to 77 or 78, wherein R ⁹ is H, -C _1-6 haloalkyl, -C _1-6 alkyl, -C _2-6 alkenyl, -C _{2 -6} alkynyl,-(CH ₂ CH ₂ O) _n R ^a , -C (= 0) R ^a , -C (= 0) OR ^a , -C (= 0) NR ^a R ^b , -C _{1- 6} alkyl-OC _1-6 alkyl, 6- to 12-membered aryl or heteroaryl, 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, 3- to 12-membered cycloalkenyl, 3- Independently selected from membered to 12-membered monocyclic or bicyclic cycloalkyl, or 3-membered to 12-membered monocyclic or bicyclic heterocycloalkyl group, and heteroaryl, spiroheterocycloalkyl and heterocycloalkyl groups are independent from O, N or S The cycloalkyl, spirocycloalkyl, spirterocycloalkyl, and heterocycloalkyl groups having 1, 2, 3 or 4 heteroatoms selected from may further comprise a C═O group, and further spiroheterocycloalkyl and heterocycle Alkyl group is S = O or compounds that may contain SO _2, or a stereoisomer, chemical to allow its pharmaceutically acceptable salt, or pharmaceutically acceptable salt of the stereoisomer thereof.

80. The pharmaceutically acceptable compound of any one of embodiments 1, 2, 68 to 78 or 79, wherein R ⁹ is -CH ₃ , or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof. Possible salts.

81. The pharmaceutical of any of embodiments 1, 2, 68 to 78 or 79, wherein R ⁹ is -CH ₂ CH ₃ , or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof. Acceptable salts.

82. The compound of any of embodiments 1, 2, 68 to 80 or 81, wherein R ^9A is H, C _1-6 haloalkyl, C _1-6 alkyl, -C _2-6 alkenyl, -C _2-6 Alkynyl- (CH ₂ CH ₂ O) _n R ^a , -SO ₂ R ^a , -C (= 0) R ^a , -C (= 0) OR ^a , -C (= 0) NR ^a R ^b ,- NR ^a R ^b , -N = N = N, -C _1-6 alkyl-OC _1-6 alkyl, 6- to 12-membered aryl, 6- to 12-membered heteroaryl, 5- to 12- Independent from one-spirocycloalkyl or spiroheterocycloalkyl, 3-membered to 12-membered cycloalkenyl, 3-membered to 12-membered monocyclic or bicyclic cycloalkyl, or 3-membered to 12-membered monocyclic or bicyclic heterocycloalkyl group Wherein the heteroaryl, spiroheterocycloalkyl and heterocycloalkyl groups have 1, 2, 3, or 4 heteroatoms independently selected from O, N or S, and cycloalkyl, spirocycloalkyl, spirocyclocycloalkyl , And heterocycloalkyl groups may comprise C═O groups, further Heterocycloalkyl and heterocycloalkyl group is S = O or compounds that may contain SO _2, or a stereoisomer, chemical to allow its pharmaceutically acceptable salt, or pharmaceutically acceptable salt of the stereoisomer thereof.

83. The compound of any of embodiments 1, 2, 68 to 81 or 82, wherein R ^9A is —C _1-6 alkyl, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a medicament thereof Scholarly acceptable salts.

84. The compound of any one of embodiments 1, 2, 68 to 81 or 82, wherein R ^9A is -C (= 0) R ^a , or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof Pharmaceutically acceptable salts of.

85. The compound of any of embodiments 1, 2, 68 to 81 or 82, wherein R ^9A is a 3- to 12-membered monocyclic or bicyclic heterocycloalkyl group, and the heterocycloalkyl group is independently selected from O, N or S A compound having 1, 2, 3, or 4 heteroatoms, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof.

86. The compound of any one of embodiments 1, 2, 68 to 82 or 85, wherein R ^9A is a 3- to 12-membered monocyclic heterocycloalkyl group, and the heterocycloalkyl group is independently selected from O or N; A compound having 3, or 4 heteroatoms, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof.

87. The compound of any one of embodiments 1, 2, 68 to 82 or 85 to 86, wherein the 3- to 12-membered monocyclic heterocycloalkyl R ^9A group is unsubstituted or substituted with OH, halo, -NR ^c R ^d , -C _1-6 alkyl, -C ₂ -C ₆ alkenyl, -C ₂ -C ₆ alkynyl, -OC _1-6 alkyl, -C _1-6 alkyl-OH, -C _1-6 alkyl-OC _1-6 Alkyl, C _1-6 haloalkyl, -O-haloC _1-6 alkyl, -SO ₂ R ^c , -CN, -C (= 0) NR ^c R ^d , -C (= 0) R ^c , -OC (= O) R ^a , -C (= O) OR ^c , 6- to 12-membered aryl, 6- to 12-membered heteroaryl, 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl 1, 2, 3 or 4 independently selected from 3-membered to 12-membered cycloalkenyl, 3-membered to 12-membered monocyclic or bicyclic cycloalkyl, or 3-membered to 12-membered monocyclic or bicyclic heterocycloalkyl group two R ¹⁰ substituents and may be substituted, a heteroaryl group, spiro-heterocycloalkyl, and heterocycloalkyl group is O, N or S is selected independently from 1, 2, 3 Has 4 heteroatoms, cycloalkyl, spiro cycloalkyl, spiro-heterocycloalkyl, and heterocycloalkyl group may comprise a group C = O, adding a spiro heterocycloalkyl and heterocycloalkyl group is S = O or SO A compound that may include ₂ , or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of its stereoisomer.

88. The compound of any one of embodiments 1, 2, 68 to 82 or 85 to 86, wherein 1, 2, 3 or 4 R ¹⁰ substituents are —C _1-6 alkyl or 3- to 12-membered monocyclic heterocyclo A compound having one, two, three, or four heteroatoms independently selected from an alkyl group, the heterocycloalkyl group independently selected from O, N, or S, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a Pharmaceutically acceptable salts of stereoisomers.

89. The compound of any one of embodiments 1, 2, 68 to 82 or 85 to 88, wherein R ¹⁰ is —C _1-6 alkyl, or a stereoisomer, pharmaceutically acceptable salt thereof, or stereoisomer thereof. Pharmaceutically acceptable salts of.

90. The compound of any one of embodiments 1, 2, 68 to 82 or 85 to 88, wherein R ¹⁰ is a 3- to 12-membered monocyclic heterocycloalkyl group, and the heterocycloalkyl group is independently selected from O, N or S A compound having 1, 2, 3, or 4 heteroatoms, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof.

91. The compound of any of embodiments 1, 2, 68 to 82 or 85, wherein R ^9A is a 5- to 12-membered bicyclic heterocycloalkyl group, and the heterocycloalkyl group is independently selected from O or N; A compound having 3, or 4 heteroatoms, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof.

92. The compound of any of embodiments 1, 2 or 68 to 82, wherein R ^9A is

으로부터 독립적으로 선택되는 화합물, 또는 이의 입체이성질체, 이의 약제학적으로 허용 가능한 염, 또는 이의 입체이성질체의 약제학적으로 허용 가능한 염.

A compound selected independently from, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof.

93. Another embodiment of the present invention includes a compound of embodiment 1 or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of stereoisomer thereof, wherein the compound of Formula I ' III '

Formula III ';

With R ⁴ , R ⁵ , R ⁹ and R ^9A as defined above.

94. Another embodiment of the present invention includes a compound of embodiment 1, 2 or 93, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of stereoisomer thereof, wherein Compound of Formula III'a

 Formula III'a;

Has

95. The compound of any one of embodiments 1, 2, or 93 to 94, wherein R ⁴ is H, -C _1-6 alkyl, -C _1-6 alkylhalo, -C _1-6 alkyl-OC _1-6 Independently selected from alkyl, or — (CH ₂ CH ₂ O) _n R ^a , wherein —C _1-6 alkyl is unsubstituted or substituted —OH, — (═O), phenyl, —O—SiR ^a R ^b R ^c , -NR ^a R ^b , 3- to 12-membered cycloalkyl, or 3- to 12-membered monocyclic or bicyclic having 1, 2, 3, or 4 heteroatoms independently selected from O, N or S A compound substituted with heterocycloalkyl, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof.

96. The compound of any one of embodiments 1, 2, or 93 to 95, wherein R ⁴ is -CH ₃ , or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of the stereoisomer thereof salt.

97. The compound of embodiment 1, 2, or 93 to 95, wherein R ⁴ is —CH ₂ CH ₂ OCH ₃ , or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a medicament thereof Scholarly acceptable salts.

98. The compound of any one of embodiments 1, 2, or 93 to 97, wherein R ⁵ is H or —C _1-6 alkyl, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof Pharmaceutically acceptable salts.

99. The pharmaceutically acceptable compound of any one of embodiments 1, 2, or 93 to 98, wherein R ⁵ is -CH ₃ , or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof. salt.

100. The compound of any one of embodiments 1,2 or 93 to 98, wherein R ⁵ is H, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of stereoisomer thereof.

101. The compound of any of embodiments 1, 2, or 93 to 100, wherein R ⁶ is H or —C _1-6 alkyl, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof; Pharmaceutically acceptable salts.

102. The compound of any one of embodiments 1, 2, or 93 to 101, wherein R ⁶ is -CH ₃ , or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of the stereoisomer thereof. salt.

103. The compound of any one of embodiments 1, 2 or 93 to 101, wherein R ⁶ is H, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of stereoisomer thereof.

104. The compound of any one of embodiments 1, 2 or 93 to 103, wherein R ⁹ is H, -C _1-6 haloalkyl, -C _1-6 alkyl, -C _2-6 alkenyl, -C _2-6 Alkynyl,-(CH ₂ CH ₂ O) _n R ^a , -C (= 0) R ^a , -C (= 0) OR ^a , -C (= 0) NR ^a R ^b , -C _1-6 alkyl -OC _1-6 alkyl, 6- to 12-membered aryl or heteroaryl, 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, 3- to 12-membered cycloalkenyl, 3-membered to Independently selected from 12-membered monocyclic or bicyclic cycloalkyl, or 3-membered to 12-membered monocyclic or bicyclic heterocycloalkyl group, and heteroaryl, spiroheterocycloalkyl and heterocycloalkyl groups independently selected from O, N or S Having 1, 2, 3 or 4 heteroatoms, the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkyl groups can comprise C═O groups, and further spiroheterocycloalkyl and heterocyclo The alkyl group may comprise S═O or SO ₂ , or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of stereoisomer thereof.

105. The compound of any one of embodiments 1, 2, or 93 to 104, wherein R ⁹ is -CH ₃ , or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of the stereoisomer thereof. salt.

106. The pharmaceutical of any of embodiments 1, 2, or 93 to 104, wherein R ⁹ is —CH ₂ CH ₃ , or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof. Acceptable salts.

107. The compound of any one of embodiments 1, 2, or 93 to 104, wherein R ⁹ is -H, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of stereoisomer thereof. .

108. The compound of any one of embodiments 1, 2 or 93 to 107, wherein R ^9A is H, C _1-6 haloalkyl, C _1-6 alkyl, —C _2-6 alkenyl, — (CH ₂ CH ₂ O ) _n R ^a , -SO ₂ R ^a , -C (= O) R ^a , -C (= O) OR ^a , -C (= O) NR ^a R ^b , -NR ^a R ^b , -N = N = N, -C _1-6 alkyl-OC _1-6 alkyl, 6- to 12-membered aryl, 6- to 12-membered heteroaryl, 5- to 10-membered spirocycloalkyl or spiroheterocycloalkyl , Independently selected from 3-membered to 12-membered cycloalkenyl, 3-membered to 12-membered monocyclic or bicyclic cycloalkyl, or 3-membered to 12-membered monocyclic or bicyclic heterocycloalkyl group, heteroaryl, spirohetero Cycloalkyl and heterocycloalkyl groups have 1, 2, 3, or 4 heteroatoms independently selected from O, N or S, and cycloalkyl, spirocycloalkyl, spirocyclocycloalkyl, and heterocycloalkyl groups are C═O Groups, and may further comprise spirohterocycles Alkyl and heterocycloalkyl group is S = O or compounds that may contain SO _2, or a stereoisomer, chemical to allow its pharmaceutically acceptable salt, or pharmaceutically acceptable salt of the stereoisomer thereof.

109. The compound of any one of embodiments 1, 2, or 93 to 108, wherein R ^9A is -C _1-6 alkyl, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof Acceptable salts.

110. The compound of any of embodiments 1, 2 or 93 to 108, wherein R ^9A is -C (= 0) R ^a , or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof Scholarly acceptable salts.

111. The compound of any of embodiments 1, 2 or 93 to 108, wherein R ^9A is a 3- to 12-membered monocyclic or bicyclic heterocycloalkyl group, and the heterocycloalkyl group is 1, independently selected from O, N or S, Compounds having 2, 3, or 4 heteroatoms, or stereoisomers thereof, pharmaceutically acceptable salts thereof, or pharmaceutically acceptable salts of stereoisomers thereof.

112. The compound of any of embodiments 1, 2, 93 to 108 or 111, wherein R ^9A is a 3- to 12-membered monocyclic heterocycloalkyl group, and the heterocycloalkyl group is independently selected from O or N; A compound having 3, or 4 heteroatoms, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof.

113. The compound of any one of embodiments 1, 2, 93 to 108 or 112, wherein the 3- to 12-membered monocyclic heterocycloalkyl R ^9A group is unsubstituted or substituted with OH, halo, -NR ^c R ^d , -C _{1- 6} alkyl, -C ₂ -C ₆ alkenyl, -C ₂ -C ₆ alkynyl, -OC _1-6 alkyl, -C _1-6 alkyl-OH, -C _1-6 alkyl-OC _1-6 alkyl, C _1-6 haloalkyl, —O-haloC _1-6 alkyl, —SO ₂ R ^c , —CN, —C (═O) NR ^c R ^d , —C (═O) R ^c , -OC (= O) R ^a , -C (= 0) OR ^c , 6- to 12-membered aryl, 6- to 12-membered heteroaryl, 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, 3 1, 2, 3 or 4 R independently selected from -membered to 12-membered cycloalkenyl, 3-membered to 12-membered monocyclic or bicyclic cycloalkyl, or 3-membered to 12-membered monocyclic or bicyclic heterocycloalkyl group ¹⁰ substituents that can be substituted with a heteroaryl, spirterocycloalkyl, and heterocycloalkyl group independently selected from O, N or S 1, 2, 3 or 4 Heteroatoms, the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkyl groups may comprise C═O groups, and further the spiroheterocycloalkyl and heterocycloalkyl groups may represent S═O or SO ₂ Compounds that may include, or stereoisomers thereof, pharmaceutically acceptable salts thereof, or pharmaceutically acceptable salts of stereoisomers thereof.

114. The compound of any of embodiments 1, 2, 93 to 108 or 112 to 113, wherein 1, 2, 3 or 4 R ¹⁰ substituents are —C _1-6 alkyl or 3- to 12-membered monocyclic heterocyclo A compound having one, two, three, or four heteroatoms independently selected from an alkyl group, the heterocycloalkyl group independently selected from O, N, or S, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a Pharmaceutically acceptable salts of stereoisomers.

115. The compound of any one of embodiments 1, 2, 93 to 108 or 112 to 114, wherein R ¹⁰ is —C _1-6 alkyl, or a stereoisomer, pharmaceutically acceptable salt thereof, or stereoisomer thereof. Pharmaceutically acceptable salts of.

116. The compound of any of embodiments 1, 2, 93 to 108 or 112 to 113, wherein R ¹⁰ is a 3- to 12-membered monocyclic heterocycloalkyl group, and the heterocycloalkyl group is independently selected from O, N or S A compound having 1, 2, 3, or 4 heteroatoms, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof.

117. The compound of any of embodiments 1, 2, 93 to 108 or 111, wherein R ^9A is a 5- to 12-membered bicyclic heterocycloalkyl group, and the heterocycloalkyl group is independently selected from O or N; A compound having 3, or 4 heteroatoms, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof.

118. The compound of any of embodiments 1, 2, or 93 to 108, wherein R ^9A is

으로부터 독립적으로 선택되는 화합물, 또는 이의 입체이성질체, 이의 약제학적으로 허용 가능한 염, 또는 이의 입체이성질체의 약제학적으로 허용 가능한 염.

A compound selected independently from, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof.

119. Another embodiment of the present invention includes a compound of embodiment 1 or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of stereoisomer thereof, wherein the compound of Formula I 'is IV '

Formula IV ';

With R ⁴ , R ⁵ , R ⁹ and R ^9A as defined above.

120. Another embodiment of the invention includes a compound of embodiment 1, 2 or 119, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of stereoisomer thereof, wherein Compound of Formula IV'a

Formula IV'a;

Has

121. The compound of any of embodiments 1, 2, or 119 to 120, wherein R ⁴ is H, -C _1-6 alkyl, -C _1-6 alkylhalo, -C _1-6 alkyl-OC _1-6 Independently selected from alkyl, or — (CH ₂ CH ₂ O) _n R ^a , wherein —C _1-6 alkyl is unsubstituted or substituted —OH, — (═O), phenyl, —O—SiR ^a R ^b R ^c , -NR ^a R ^b , 3- to 12-membered cycloalkyl, or 3- to 12-membered monocyclic or bicyclic having 1, 2, 3, or 4 heteroatoms independently selected from O, N or S A compound substituted with heterocycloalkyl, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof.

122. The compound of any one of embodiments 1, 2, or 119 to 121, wherein R ⁴ is -CH ₃ , or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of the stereoisomer thereof. salt.

123. The compound of any of embodiments 1, 2, or 119 to 121, wherein R ⁴ is -CH ₂ CH ₂ OCH ₃ , or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a medicament thereof Scholarly acceptable salts.

124. The compound of any of embodiments 1, 2, or 119 to 123, wherein R ⁵ is H or -C _1-6 alkyl, or a stereoisomer, pharmaceutically acceptable salt thereof, or stereoisomer thereof. Pharmaceutically acceptable salts.

125. The compound of any one of embodiments 1, 2, or 119 to 124, wherein R ⁵ is -CH ₃ , or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of the stereoisomer thereof. salt.

126. The compound of any of embodiments 1, 2 or 119 to 125, wherein R ⁵ is H, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of stereoisomer thereof.

127. The compound of any of embodiments 1, 2, or 119 to 126, wherein R ⁶ is H or -C _1-6 alkyl, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof; Pharmaceutically acceptable salts.

128. The compound of any one of embodiments 1, 2, or 119 to 127, wherein R ⁶ is -CH ₃ , or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of the stereoisomer thereof. salt.

129. The compound of any of embodiments 1,2 or 119 to 127, wherein R ⁶ is H, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of stereoisomer thereof.

130. The compound of any of embodiments 1, 2 or 119 to 129, wherein R ⁹ is H, -C _1-6 haloalkyl, -C _1-6 alkyl, -C _2-6 alkenyl,-(CH ₂ CH ₂ O) _n R ^a , -C (= 0) R ^a , -C (= 0) OR ^a , -C (= 0) NR ^a R ^b , -C _1-6 alkyl-OC _1-6 alkyl, 6 -Membered to 12-membered aryl or heteroaryl, 5-membered to 12-membered spirocycloalkyl or spiroheterocycloalkyl, 3-membered to 12-membered cycloalkenyl, 3-membered to 12-membered monocyclic or bicyclic cycloalkyl Or 1, 2, 3 or 4 independently selected from 3- to 12-membered monocyclic or bicyclic heterocycloalkyl groups, and heteroaryl, spiroheterocycloalkyl and heterocycloalkyl groups independently selected from O, N or S Having a heteroatom, cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkyl groups may comprise C═O groups, and further, spiroheterocycloalkyl and heterocycloalkyl groups may contain S═O Or a compound which may comprise SO ₂ , or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of its stereoisomer.

131. The compound of any one of embodiments 1, 2, or 119 to 130, wherein R ⁹ is -CH ₃ , or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of the stereoisomer thereof. salt.

132. The pharmaceutical composition of any one of embodiments 1, 2, or 119 to 130, wherein R ⁹ is -CH ₂ CH ₃ , or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof. Acceptable salts.

133. The compound of any of embodiments 1, 2 or 119 to 132, wherein R ^9A is H, C _1-6 haloalkyl, C _1-6 alkyl, -C _2-6 alkenyl,-(CH ₂ CH ₂ O ) _n R ^a , -SO ₂ R ^a , -C (= O) R ^a , -C (= O) OR ^a , -C (= O) NR ^a R ^b , -NR ^a R ^b , -N = N = N, -C _1-6 alkyl-OC _1-6 alkyl, 6- to 12-membered aryl, 6- to 12-membered heteroaryl, 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl , Independently selected from 3-membered to 12-membered cycloalkenyl, 3-membered to 12-membered monocyclic or bicyclic cycloalkyl, or 3-membered to 12-membered monocyclic or bicyclic heterocycloalkyl group, heteroaryl, spirohetero Cycloalkyl and heterocycloalkyl groups have 1, 2, 3, or 4 heteroatoms independently selected from O, N or S, and cycloalkyl, spirocycloalkyl, spirocyclocycloalkyl, and heterocycloalkyl groups are C═O Groups, and may further comprise spirohterocycles The roalkyl and heterocycloalkyl groups may comprise S═O or SO ₂ , or stereoisomers thereof, pharmaceutically acceptable salts thereof, or pharmaceutically acceptable salts of stereoisomers thereof.

134. The compound of any one of embodiments 1, 2, or 119 to 133, wherein R ^9A is -C _1-6 alkyl, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof Acceptable salts.

135. The compound of any one of embodiments 1, 2 or 119 to 113, wherein R ^9A is -C (= 0) R ^a , or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof Scholarly acceptable salts.

136. The compound of any one of embodiments 1, 2 or 119 to 133, wherein R ^9A is a 3- to 12-membered monocyclic or bicyclic heterocycloalkyl group, wherein the heterocycloalkyl group is 1, independently selected from O, N or S; Compounds having 2, 3, or 4 heteroatoms, or stereoisomers thereof, pharmaceutically acceptable salts thereof, or pharmaceutically acceptable salts of stereoisomers thereof.

137. The compound of any of embodiments 1, 2, 119 to 133 or 136, wherein R ^9A is a 3- to 12-membered monocyclic heterocycloalkyl group, and the heterocycloalkyl group is independently selected from O or N; A compound having 3, or 4 heteroatoms, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof.

138. The compound of any one of embodiments 1, 2, 119 to 133, or 136 to 137, wherein the 3- to 12-membered monocyclic heterocycloalkyl R ^9A group is unsubstituted or substituted with OH, halo, -NR ^c R ^d ,- C _1-6 alkyl, -C ₂ -C ₆ alkenyl, -C ₂ -C ₆ alkynyl, -OC _1-6 alkyl, -C _1-6 alkyl-OH, -C _1-6 alkyl-OC _{1- 6} alkyl, C _1-6 haloalkyl, -O-haloC _1-6 alkyl, -SO ₂ R ^c , -CN, -C (= 0) NR ^c R ^d , -C (= 0) R ^c ,- OC (= 0) R ^a , -C (= 0) OR ^c , 6- to 12-membered aryl, 6- to 12-membered heteroaryl, 5- to 12-membered spirocycloalkyl or spiroheterocyclo 1, 2, 3 or independently selected from alkyl, 3- to 12-membered cycloalkenyl, 3- to 12-membered monocyclic or bicyclic cycloalkyl, or 3- to 12-membered monocyclic or bicyclic heterocycloalkyl group A heteroaryl, a spirterocycloalkyl, and a heterocycloalkyl group may be substituted with four R ¹⁰ substituents, independently selected from O, N or S, Having 2, 3 or 4 heteroatoms, the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkyl groups may comprise a C═O group, and further, the spiroheterocycloalkyl and heterocycloalkyl groups may have S═ A compound that may comprise O or SO ₂ , or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of its stereoisomer.

139. The compound of any of embodiments 1, 2, 119 to 133, or 136 to 138, wherein the 1, 2, 3 or 4 R ¹⁰ substituents are -C _1-6 alkyl or 3- to 12-membered monocyclic hetero A compound having one, two, three, or four heteroatoms independently selected from a cycloalkyl group, the heterocycloalkyl group independently selected from O, N, or S, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or Pharmaceutically acceptable salts of its stereoisomers.

140. The compound of any one of embodiments 1, 2, 119 to 133, or 136 to 139, wherein R ¹⁰ is —C _1-6 alkyl, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a steric thereof Pharmaceutically acceptable salts of the isomers.

141. The compound of any of embodiments 1, 2, 119 to 133, or 136 to 139, wherein R ¹⁰ is a 3- to 12-membered monocyclic heterocycloalkyl group, and the heterocycloalkyl group is independently from O, N or S A compound having 1, 2, 3, or 4 heteroatoms selected, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of its stereoisomer.

142. The compound of any of embodiments 1, 2, 119 to 133, or 136, wherein R ^9A is a 5- to 12-membered bicyclic heterocycloalkyl group, and the heterocycloalkyl group is 1, 2 independently selected from O or N , Compounds having 3, or 4 heteroatoms, or stereoisomers thereof, pharmaceutically acceptable salts thereof, or pharmaceutically acceptable salts of stereoisomers thereof.

143. The compound of any of embodiments 68 to 70, wherein R ^9A is

A compound selected independently from, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof.

144. Another embodiment of the present invention includes a compound of embodiment 1 or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of stereoisomer thereof, wherein the compound is

Is selected from.

145. The compound of embodiment 144 or a pharmaceutically acceptable salt thereof.

146. Another embodiment of the present invention includes a compound of embodiment 1 or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of stereoisomer thereof, wherein the compound is

Is selected from.

147. The compound of embodiment 146 or a pharmaceutically acceptable salt thereof.

148. Another embodiment of the present invention includes a pharmaceutical composition comprising a compound of any one of embodiments 1-147 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.

149. Another embodiment of the invention includes a method of treating cancer, the method comprising a method for treating a patient in need thereof with a therapeutically effective amount of a compound of any one of embodiments 1 to 147 or a pharmaceutically acceptable salt thereof Administering.

150. The method of embodiment 149, wherein the cancer is a hematologic malignancy.

151. The cancer of embodiment 149, wherein the cancer consists of breast cancer, colon cancer, skin cancer, melanoma, ovarian cancer, kidney cancer, lung cancer, non-small cell lung cancer, lymphoma, non-Hodgkin's lymphoma, myeloma, multiple myeloma, leukemia, and acute myeloid leukemia Selected from the group.

152. The method of embodiment 149, wherein the cancer is multiple myeloma.

153. The method of embodiment 149, further comprising administering a therapeutically effective amount of a pharmaceutically active additional compound to the patient in need thereof.

154. The method of embodiment 153, wherein the further pharmaceutically active compound is carfilzomib.

155. The method of embodiment 153, wherein the further pharmaceutically active compound is Venetoclarks.

156. The method of embodiment 153, wherein the further pharmaceutically active compound is cytarabine.

157. Another embodiment of the present invention includes the use of a compound according to any one of embodiments 1 to 147 in treating a cancer in a subject.

158. Another embodiment of the invention includes a compound according to any one of embodiments 1 to 147 in the manufacture of a medicament for the treatment of cancer.

159. The compound of embodiment 158, wherein the cancer is a hematologic malignancy.

160. The cancer cell of embodiment 158, wherein the cancer consists of breast cancer, colon cancer, skin cancer, melanoma, ovarian cancer, kidney cancer, lung cancer, non-small cell lung cancer, lymphoma, non-Hodgkin's lymphoma, myeloma, multiple myeloma, leukemia, and acute myeloid leukemia Compound selected from the group.

161. The compound of embodiment 158, wherein the cancer is multiple myeloma.

162. The compound of embodiment 158, wherein the cancer is acute myeloid leukemia.

163. The compound of embodiment 158, wherein the cancer is non-Hodgkin's lymphoma.

Embodiment B

The embodiments listed below are presented in numbered form for convenience and again for ease of reference and clarity when referring to a number of embodiments.

In a first embodiment, the invention is a compound of formula

Formula I;

Stereoisomers thereof, pharmaceutically acceptable salts thereof, or pharmaceutically acceptable salts of stereoisomers thereof,

In the formula,

Z is C or N;

Q is O, S, CR ^WA R ^WB , or NR ^a R ^b ;

W is CR ^WA R ^WB , —C═O or absent;

R ^WA and R ^WB are independently selected from H, -C _1-3 alkyl, -C _2-3 alkenyl, -C _2-3 alkynyl, halo, -OH, or -OC _1-3 alkyl;

로 표시되는 b는 시스 또는 트랜스일 수 있는 단일 또는 이중 화학 결합이고; symbol

B is a single or double chemical bond which may be cis or trans;

R ¹ is H, halo, C _1-6 alkylhalo, C _1-6 alkyl, C _2-6 alkenyl,-(CH ₂ CH ₂ O) _n R ^a , -SO ₂ R ^a , -C (= O) R ^a , -C (= 0) OR ^a , or -C (= 0) NR ^a R ^b ;

R ² is H, halo, C _1-6 haloalkyl, C _1-6 alkyl, OC _1-6 alkyl, C _2-6 alkenyl, C _1-6 alkenylene, -C _1-6 alkyl-OC _{1- 6} alkyl,-(CH ₂ CH ₂ O) _n R _a , -SO ₂ R ^a , -C (= 0) R ^a , -C (= 0) OR ^a , -OC (= 0) R ^a , -C (═O) NR ^a R ^b , 6- to 12-membered aryl or heteroaryl, 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, or 3- to 12-membered cycloalkenyl, 3 -Membered to 12-membered monocyclic or bicyclic cycloalkyl, or 3-membered to 12-membered monocyclic or bicyclic heterocycloalkyl group, wherein the heteroaryl, spiroheterocycloalkyl or heterocycloalkyl group is independently from O, N or S With 1, 2, 3 or 4 heteroatoms selected, the cycloalkyl, spirocycloalkyl, spirocyclocycloalkyl, and heterocycloalkyl groups can comprise C═O groups, further spiroheterocycloalkyl and heterocycloalkyl groups Is S = O or SO ² May include;

R ³ is H, —C _1-6 alkylhalo, —C _1-6 alkyl, —C _2-6 alkenyl, — (CH ₂ CH ₂ O) _n R ^a , —C (═O) R ^a , -C (= 0) OR ^a , or -C (= 0) NR ^a R ^b ;

R ^2B , R ^2C , R ⁴ , R ⁵ , R ⁶ , R ⁷ , and R ⁸ are each H, halo, —C _1-6 haloalkyl, —C _1-6 alkyl, —OC _1-6 alkyl, — C _2-6 alkenyl, -C _1-6 alkyl-OC _1-6 alkyl,-(CH ₂ CH ₂ O) _n R ^a , -SO ₂ R ^a , -C (= O) R ^a, -C ( = O) OR ^a , -OC (= O) R ^a , -C (= O) NR ^a R ^b , 6- to 12-membered aryl or heteroaryl, 5- to 12-membered spirocycloalkyl or spiro Heteroaryl, independently selected from heterocycloalkyl, 3- to 12-membered cycloalkenyl, 3- to 12-membered monocyclic or bicyclic cycloalkyl, or 3- to 12-membered monocyclic or bicyclic heterocycloalkyl group, heteroaryl , The spiroheterocycloalkyl and heterocycloalkyl groups have 1, 2, 3 or 4 heteroatoms independently selected from O, N or S, and the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkyl groups are C May comprise a ═O group, and further comprises spiroheterocycloalkyl and heterocy The chloroalkyl group may comprise S═O or SO ₂ ;

Alternatively, R ³ and R ⁴ together with the atoms to which they are attached form a 5-membered to 12-membered ring, wherein in addition to the S and N atoms present in the ring, a heteroatom selected from N, O or S atoms is optionally To form a containing ring, the ring may optionally contain at least one double bond, and the ring may be substituted with 0, 1, 2, or 3 R ^3A substituents;

R ^3A is H, halo, -OH, C _1-6 haloalkyl, C _1-6 alkyl, OC _1-6 alkyl, C _2-6 alkenyl, -C _1-6 alkyl -OC _1-6 alkyl,- (CH ₂ CH ₂ O) _n R ^a , -SO ₂ R ^a , -C (= 0) R ^a, -C (= 0) OR ^a , -OC (= 0) R ^a , or -C (= 0) ) NR ^a R ^b ;

Each of R ^4A , R ^5A , R ^6A , R ^7A , and R ^8A is independently selected from H, OH, halo, or —C _1-6 alkyl;

R ^7A and R ^8A are absent when b is a double chemical bond;

Alternatively, R ⁷ and R ⁸ may form a 3- to 12-membered ring together with the atoms to which they are attached, and the ring may optionally contain at least one double bond;

R ⁹ is H, OH,-(= O), -C _1-6 haloalkyl, -C _1-6 alkyl, -C _1-6 alkenylene,-(CH ₂ CH ₂ O) _n R ^a , -C (═O) R ^a, —C (═O) OR ^a , —C (═O) NR ^a R ^b , —C _1-6 alkyl-OC _1-6 alkyl, cyano, 6- to 12-membered Aryl or heteroaryl, 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, 3- to 12-membered cycloalkenyl, 3- to 12-membered monocyclic or bicyclic cycloalkyl, or 3-membered to Independently selected from a 12-membered monocyclic or bicyclic heterocycloalkyl group, a heteroaryl, spiroheterocycloalkyl or heterocycloalkyl group has 1, 2, 3 or 4 heteroatoms independently selected from O, N or S, and cyclo Alkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkyl groups may comprise C═O groups, and further spiroheterocycloalkyl and heterocycloalkyl groups may comprise S═O or SO ₂ ;

R ^9A is H, -OH, halo, cyano, -C _1-6 haloalkyl, -C _1-6 alkyl, -C ₂ -C ₆ alkenyl, -C ₂ -C _{6 alkynyl} , -C _{1- 6} alkenylene,-(CH ₂ CH ₂ O) _n R ^a , -P (= O) OR ^a OR ^b , -CSR ^a , -CS (= O) R ^a , -SR ^a , -SOR ^a , -OSO ₂ R ^a , -SO ₂ R ^a ,-(CH ₂ CH ₂ O) _n CH ₃ ,-(= O), -C (= O), -C (= O) R ^a , -C (= O) OR ^a , -C (= 0) NR ^a R ^b , -CH ₂ -NR ^a R ^b , -NR ^a R ^b , -C _1-6 alkyl-OC _1-6 alkyl, -OC _1-6 alkyl,- OC _1-6 alkyl-OC _1-6 alkyl, phenyl, 6- to 12-membered aryl, 6- to 12-membered heteroaryl, 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, 3 Independently selected from -membered to 12-membered cycloalkenyl, 3-membered to 12-membered monocyclic or bicyclic cycloalkyl, or 3-membered to 12-membered monocyclic or bicyclic heterocycloalkyl group, heteroaryl, spiroheterocycloalkyl And the heterocycloalkyl group has 1, 2, 3 or 4 heteroatoms independently selected from O, N or S, cycloal , Spiro cycloalkyl, spiro-heterocycloalkyl, and heterocycloalkyl group is further number, and comprise a group may contain a double bond and the C = O spiro heterocycloalkyl and heterocycloalkyl group contains S = O or SO ₂ Can do it;

R ^9A is not H when W is absent;

The aryl, heteroaryl, cycloalkyl, heterocycloalkyl, spirocycloalkyl and ^{spirterocycloalkyl} groups of the R ^9A substituent are unsubstituted or substituted with OH, halo, -NR ^c R ^d , -C _1-6 alkyl, -C ₂ -C ₆ alkenyl, -C ₂ -C ₆ alkynyl, -OC _1-6 alkyl, -C _1-6 alkyl-OH, -C _1-6 alkyl-OC _1-6 alkyl, C _1-6 haloalkyl,- O-haloC _1-6 alkyl, -SO ₂ R ^c , -CN, -C (= 0) NR ^c R ^d , -C (= 0) R ^c , -OC (= 0) R ^a , -C ( = O) OR ^c , 6- to 12-membered aryl, 6- to 12-membered heteroaryl, 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, 3- to 12-membered cycloal May be substituted with 1, 2, 3 or 4 R ¹⁰ substituents independently selected from kenyl, 3- to 12-membered monocyclic or bicyclic cycloalkyl, or 3- to 12-membered monocyclic or bicyclic heterocycloalkyl groups, Heteroaryl, spiroheterocycloalkyl, and heterocycloalkyl groups are 0, independently selected from O, N or S, Having 1, 2, 3 or 4 heteroatoms, the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkyl groups can comprise C═O groups, and further the spiroheterocycloalkyl and heterocycloalkyl groups May comprise S═O or SO ₂ ;

Alternatively, R ⁷ and R ^9A together with the atoms to which they are attached may form a 3-membered to 12-membered ring, and the ring may optionally contain at least one double bond;

Alternatively, R ⁹ and R ^9A form a 3-membered to 12-membered monocyclic or bicyclic ring together with Q, W and C to which W and Q bond, a hetero group other than Q selected from N, O or S A ring optionally containing atoms may be formed, the ring may contain a double bond, the ring may optionally include a C═O group, and further the ring may be substituted by 1, 2, or 3 R ¹¹ substituents May be optionally substituted;

R ¹¹ is H, -OH, halo, -C _1-6 alkyl, -OC _1-6 alkyl, -C _1-6 alkyl-OH, -C _1-6 alkyl-OC _1-6 alkyl, -C _{1- 6} haloalkyl, -O-haloC _1-6 alkyl, -SO ₂ R ^c , -CN, -NR ^c R ^d , -C (= 0) NR ^c R ^d , -C (= 0) R ^c ,- OC (= 0) R ^c , -C (= 0) OR ^c , 6- to 12-membered aryl or heteroaryl, 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, 3- to 12 Independently selected from -membered cycloalkenyl, 3-membered to 12-membered monocyclic or bicyclic cycloalkyl, or 3-membered to 12-membered monocyclic or bicyclic heterocycloalkyl group, heteroaryl, spiroheterocycloalkyl, and heterocyclo The alkyl group has 1, 2, 3 or 4 heteroatoms independently selected from O, N or S, and the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkyl groups can comprise double bonds and cyclo Alkyl, spirocycloalkyl, spiroheterocycloalkyl, And the heterocycloalkyl group may comprise a C═O group, and further the spiroheterocycloalkyl and heterocycloalkyl group may comprise S═O or SO ₂ ;

R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ^4A , R ^5A , R ^6A , R ^7A , R ^8A , R ^9A C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl and —OC _1-6 alkyl of any one of the R ^WA and R ^WB substituents may be unsubstituted or substituted with OH, —OC _1-6 alkyl, -C _1-6 alkyl-OC _1-6 alkyl, halo, -O-haloC _1-6 alkyl, -CN, -NR ^a R ^b ,-(NR ^a R ^b R ^c ) _n , -OSO ₂ R ^a , -SO ₂ R ^a ,-(CH ₂ CH ₂ O) _n CH ₃ ,-(= O), -C (= O), -C (= O) R ^a , -OC (= O) R ^a , -C (= 0) OR ^a , -C (= 0) NR ^a R ^b , -O-SiR ^a R ^b R ^c , -SiR ^a R ^b R ^c , -O- (3- to 10-membered hetero Cycloalkyl), 6-membered to 12-membered aryl or heteroaryl, 5-membered to 12-membered spirocycloalkyl or spiroheterocycloalkyl, 3-membered to 12-membered cycloalkenyl, 3-membered to 12-membered Monocyclic or bicyclic cycloalkyl, or substituted by 1, 2 or 3 R ¹² substituents independently selected from 3- to 12-membered monocyclic or bicyclic heterocycloalkyl groups, heteroaryl, spi The loheterocycloalkyl and heterocycloalkyl groups have 1, 2, 3 or 4 heteroatoms independently selected from O, N or S, and the cycloalkyl, spirocycloalkyl, spirocyclocycloalkyl, and heterocycloalkyl groups are C = May comprise an O group, and further the spiroheterocycloalkyl and heterocycloalkyl groups may comprise S═O or SO ₂ ;

R ² , R ⁴ , R ⁵ , Aryl, heteroaryl, cycloalkyl, heterocycloalkyl, spirocycloalkyl and any one of R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ^9A , R ¹⁰ , R ¹¹ , R ¹² , R ^WA and R ^WB substituents and Spiroheterocycloalkyl groups are unsubstituted or substituted with OH, halo, -NR ^c R ^d , -C _1-6 alkyl, -OC _1-6 alkyl, -C _1-6 alkyl-OH, -C _1-6 alkyl-OC _{1 -6} alkyl, C _1-6 haloalkyl, -O-haloC _1-6 alkyl, -SO ₂ R ^c , -CN, -C (= 0) NR ^c R ^d , -C (= 0) R ^c , -OC (= 0) R ^a , -C (= 0) OR ^c , 6- to 12-membered aryl or heteroaryl, 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, 3-membered to With 1, 2, 3 or 4 R ¹³ substituents independently selected from 12-membered cycloalkenyl, 3- to 12-membered monocyclic or bicyclic cycloalkyl, or 3-membered to 12-membered monocyclic or bicyclic heterocycloalkyl group may be substituted, a heteroaryl group, spiro-heterocycloalkyl, heteroaryl, and cycloalkyl group of R ¹³ is O, N or S robu Independently has a selected one, two, three or four heteroatoms, heterocycloalkyl group of R ¹³ cycloalkyl, spiro cycloalkyl, and spiro heterocycloalkyl group or R ¹³ is additionally can comprise a C = O, Spiroheterocycloalkyl and heterocycloalkyl groups may comprise S═O or SO ₂ ;

Each of R ^a , R ^b , R ^c , and R ^d is independently hydrogen, OH, —C _1-6 alkyl, —C _2-6 alkenyl, —C _2-6 alkynyl, —C _1-6 alkyl -NR ¹⁴ R ¹⁴ , -NR ¹⁴ R ¹⁴ , -SO ₂ R ¹⁴ ,-(CH ₂ CH ₂ O) _n CH ₃ ,-(= O), -C (= O) R ¹⁴ , -OC (= O ) R ¹⁴ , -C (= 0) OR ¹⁴ , -C (= 0) NR ¹⁴ R ¹⁴ , -C _1-6 haloalkyl, -O-haloC _1-6 alkyl, -C _1-6 alkyl-OC _1-6 alkyl, benzyl, phenyl, -C _1-6 alkyl C (= 0) OH, -C _1-6 alkyl-C (= 0) -OC _1-6 alkyl, -C _1-6 alkyl-cycloalkyl , -C _1-6 alkyl-heterocycloalkyl, -C _1-6 alkyl-6- to 10-membered aryl, -C _1-6 alkyl-6- to 10-membered heteroaryl, 6- to 12 -Membered aryl or heteroaryl, 5-membered to 12-membered spirocycloalkyl or spiroheterocycloalkyl, or 3-membered to 12-membered cycloalkenyl, 3-membered to 12-membered monocyclic or bicyclic cycloalkyl, or 3 A -membered to 12-membered monocyclic or bicyclic heterocycloalkyl group, and heteroaryl, spirohterocycloalkyl, heterocycloalkyl group or -C _1-6 alkyl Heterocycloalkyl groups have 1, 2, 3 or 4 heteroatoms independently selected from O, N or S, and cycloalkyl, spirocycloalkyl, spiroheterocyclo of R ^a , R ^b , R ^c , and R ^d An alkyl, heterocycloalkyl group or heterocycloalkyl group or —C _1-6 alkyl-heterocycloalkyl group may comprise a double bond and may comprise a C═O group, and spiroheterocycloalkyl or heterocycloalkyl may be S═O or May include SO ₂ ;

Of R ^a, R ^b, R ^c, and R ^d of the alkyl, aryl, heteroaryl, spiro cycloalkyl, spiro-heterocycloalkyl, cycloalkyl, or heterocycloalkyl group, and R ^a, R ^b, R ^c, and R ^d The heterocycloalkyl group of a -C _1-6 alkyl-heterocycloalkyl group may be unsubstituted or substituted with 1, 2, 3, or 4 R ¹⁴ substituents, each R ¹⁴ being H, -OH, -N = N = N, halo, -C _1-6 alkyl, -C _1-6 haloalkyl, -OC _1-6 alkyl, -C _1-6 alkyl-OC _1-6 alkyl, -C _1-6 haloalkyl, -O -HaloC _1-6 alkyl, phenyl, tolyl, -C (= 0) C _1-6 alkyl, -C (= 0) OC _1-6 alkyl, N (CH ₃ ) ₂ or -SO ₂ -N (CH ₃ ) independently selected from ₂ ;

n is independently at each occurrence an integer of 1, 2, 3 or 4.

2. Another embodiment of the present invention comprises a compound of embodiment 1 or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of stereoisomer thereof, wherein the compound is represented by Formula II

Formula II;

Has

3. Another embodiment of the invention comprises a compound of any one of embodiments 1 or 2 or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of stereoisomer thereof, wherein the compound is Formula IIa

Formula IIa;

Has

4. The pharmaceutically acceptable compound of any one of embodiments 1 to 3, wherein Q is O, NR ^a NR ^b , or S, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof. salt.

5. The compound of any of embodiments 1-4, wherein Q is O, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of stereoisomer thereof.

6. The pharmaceutical composition of any one of embodiments 1-5, wherein W is CR ^WA R ^WB , -C = O or not present, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof Acceptable salts.

7. The compound of embodiment 5, wherein W is CR ^WA R ^WB , or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of stereoisomer thereof.

8. The compound of embodiment 5, wherein W is absent, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of stereoisomer thereof.

9. A method according to any one of embodiments 1 to 7, R ^WA and ^WB R is H, (= O), -C 1-3 alkyl, -C ₂ - ₃ alkenyl, -C ₂ - ₃ alkynyl, halo , -OH, or -OC ₁ - ₃ compound is independently selected from alkyl, or a stereoisomer, chemical to allow its pharmaceutically acceptable salt, or pharmaceutically acceptable salt of the stereoisomer thereof.

10. The compound of embodiment 9, wherein R ^WA and R ^WB are both H, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of stereoisomer thereof.

11. The compound of embodiment 9, wherein R ^WA is -CH ₃ , or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of stereoisomer thereof.

12. The compound of embodiment 9, wherein R ^WB is -CH ₃ , or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of stereoisomer thereof.

13. The compound of embodiment 9, wherein R ^WA is -OH and R ^WB is H, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of stereoisomer thereof.

14. The compound of any of embodiments 1-13, wherein R ¹ is a haloin compound, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of stereoisomer thereof.

15. The compound of embodiment 14, wherein R ¹ is Cl, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of stereoisomer thereof.

16. The pharmaceutical composition of any one of embodiments 1-15, wherein R ³ is a compound selected from H and -C _1-6 alkyl, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof Acceptable salts.

17. The compound of embodiment 16, wherein R ³ is H, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of stereoisomer thereof.

18. The compound of any of embodiments 1-17 wherein R ⁴ is H, -C _1-6 alkyl, -C _1-6 alkyl-OC _1-6 alkyl, -C _1-6 alkyl-OH, -C _{1 -6} alkyl-OSO ₂ CH ₃ , -C _1-6 alkyl-phenyl, or -C _1-6 alkyl- (with 5 or 6-membered) (with 1 or 2 heteroatoms independently selected from N or O) Heterocycloalkyl), or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof

으로부터 독립적으로 선택되는 화합물, 또는 이의 입체이성질체, 이의 약제학적으로 허용 가능한 염, 또는 이의 입체이성질체의 약제학적으로 허용 가능한 염.19. The compound of any of embodiments 1-18, wherein R ⁴ is H, —CH ₃ , —CH ₂ CH ₃ ,

A compound selected independently from, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof.

20. The compound of embodiment 19, wherein R ⁴ is —CH ₃ , or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of stereoisomer thereof.

21. The pharmaceutical composition of any one of embodiments 1 to 20, wherein R ⁵ is a compound selected from H or —C _1-6 alkyl, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof. Acceptable salts.

22. The compound of embodiment 21, wherein R ⁵ is -CH ₃ , or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of stereoisomer thereof.

23. The pharmaceutical composition of any one of embodiments 1 to 22, wherein R ⁶ is a compound selected from H or —C _1-6 alkyl, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof. Acceptable salts.

24. The compound of embodiment 23, wherein R ⁶ is H, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of stereoisomer thereof.

25. The compound of any of embodiments 1-24 wherein R ⁹ is H, -C _1-6 alkyl, -C _1-6 haloalkyl, -C _1-6 alkyl-OC _1-6 alkyl, -C _1- Independently selected from ₆ alkyl- (5- to 6-membered heterocycloalkyl), heterocycloalkyl has one or two heteroatoms independently selected from N or O, or -C _1-6 alkyl-phenyl, The phenyl of -C _1-6 alkyl-phenyl of the R ⁹ group is unsubstituted or substituted with one or two R ¹³ substituents selected from halo or -C _1-6 alkyl-OC _1-6 alkyl, or a steric thereof Isomers, pharmaceutically acceptable salts thereof, or pharmaceutically acceptable salts of stereoisomers thereof.

, 또는

으로부터 독립적으로 선택되는 화합물, 또는 이의 입체이성질체, 이의 약제학적으로 허용 가능한 염, 또는 이의 입체이성질체의 약제학적으로 허용 가능한 염.26. The compound of embodiment 25, wherein R ⁹ is H, -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , CH ₂ CH ₂ OCH ₃ , CH ₂ CF ₃ ,

, or

A compound selected independently from, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof.

27. The compound of embodiment 26, wherein R ⁹ is H, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of stereoisomer thereof.

28. The compound of embodiment 26, wherein R ⁹ is —C _1-6 alkyl, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of stereoisomer thereof.

29. The compound of embodiment 26, wherein R ⁹ is -CH ₃ , or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of stereoisomer thereof.

인 화합물, 또는 이의 입체이성질체, 이의 약제학적으로 허용 가능한 염, 또는 이의 입체이성질체의 약제학적으로 허용 가능한 염.30. The compound of embodiment 26, wherein R ⁹ is

Phosphorus compounds, or stereoisomers thereof, pharmaceutically acceptable salts thereof, or pharmaceutically acceptable salts of stereoisomers thereof.

31. The compound of any of embodiments 1 to 24, alternatively R ⁹ and R ^{9A together} with Q, W, and C to which W and Q bond form a 3- to 12-membered monocyclic or bicyclic ring, , A ring may optionally contain a heteroatom other than Q selected from N, O or S, the ring may contain a double bond, and the ring may optionally contain a C═O group, or a steric thereof Isomers, pharmaceutically acceptable salts thereof, or pharmaceutically acceptable salts of stereoisomers thereof.

를 형성하는 화합물, 또는 이의 입체이성질체, 이의 약제학적으로 허용 가능한 염, 또는 이의 입체이성질체의 약제학적으로 허용 가능한 염.32. The compound of embodiment 31, wherein R ⁹ and R ^9A are together with Q, W and C to which Q and W combine

Or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of its stereoisomer.

33. The compound of any of embodiments 1 to 30, wherein R ^9A is H, OH, -C _1-6 alkyl, -C ₂ -C ₆ alkenyl, -C _2-6 alkynyl, -OC _1-6 alkyl , -CH ₂ -NR ^a R ^b , -C (= O) NR ^a R ^b ,-(= O), -C (= O), C (= O) OR ^a , -C (= O) R ^a , Cyano, -C _1-6 haloalkyl, -C _1-6 alkyl-OC _1-6 alkyl, -OC _1-6 alkyl-OC _1-6 alkyl, -P (= O) OR ^a OR ^b ,- SR ^a , -OSO ₂ R ^a , -SOR ^a , -SO ₂ R ^a , 6- to 12-membered aryl or heteroaryl, 3- to 12-membered monocyclic or bicyclic cycloalkyl, or 3- to 12 -Independently selected from unsubstituted monocyclic or bicyclic heterocycloalkyl groups, aryl, heteroaryl, or heterocycloalkyl groups can have 1, 2, 3 or 4 heteroatoms independently selected from O, N or S , Cycloalkyl and heterocycloalkyl groups may contain double bonds, and further cycloalkyl and heterocycloalkyl groups may comprise C═O groups;

The aryl, heteroaryl, cycloalkyl, heterocycloalkyl groups of the R ^9A substituent are unsubstituted or substituted with OH, halo, -NR ^c R ^d , -C _1-6 alkyl, -C _1-6 alkyl-OH, -C _1-6 1, 2, 3 or 4 R ¹⁰ substituents independently selected from alkyl-OC _1-6 alkyl, cyano, -C (= 0) OR ^c , 6- to 10-membered aryl, or -SO ₂ R ^c May be substituted with;

C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, and —OC _1-6 alkyl of any one of R ^9A and R ¹⁰ substituents may be unsubstituted or substituted with OH, halo, , -OC _1-6 alkyl, -C _1-6 alkyl, -NR ^a R ^b , -SiR ^a R ^b R ^c , 6- to 12-membered aryl or heteroaryl, 3- to 12-membered monocyclic or A bicyclic cycloalkyl or substituted by 1, 2 or 3 R ¹² substituents independently selected from 3- to 12-membered monocyclic or bicyclic heterocycloalkyl groups, wherein the heteroaryl or heterocycloalkyl group is independent from O, N or S Having 1, 2, 3 or 4 heteroatoms selected from, the cycloalkyl or heterocycloalkyl group may comprise a C═O group, and further the heterocycloalkyl group may comprise S═O or SO ₂ ;

The -C _1-6 alkyl group of the R ¹⁰ substituent is unsubstituted or substituted by 1, 2 or 3 R ¹² substituents of -OC _1-6 alkyl;

The heterocycloalkyl group of the R ¹² substituent may be unsubstituted or substituted with 1, 2, 3 or 4 R ¹³ substituents independently selected from -NR ^c R ^d , or -C _1-6 alkyl;

Each of R ^a , R ^b , R ^c and R ^d is independently hydrogen, OH, —C _1-6 alkyl, — (CH ₂ CH ₂ O) _n CH ₃ , -NR ¹⁴ R ¹⁴ , -C _1-6 alkyl-NR ¹⁴ R ¹⁴ , phenyl, -C _1-6 alkyl-C (= 0) OH, -C _1-6 alkyl-C (= 0) -OC _{1- 6} alkyl, -C _1-6 alkyl-3-membered to 12-membered cycloalkyl, -C _1-6 alkyl-3-membered to 12-membered heterocycloalkyl, -C _1-6 alkyl-6-membered to 12 -Membered heteroaryl, 6- to 12-membered aryl or heteroaryl, 3- to 12-membered monocyclic or bicyclic cycloalkyl, or 3- to 12-membered monocyclic or bicyclic heterocycloalkyl group, R ^a , R Heteroaryl groups, heterocycloalkyl groups of ^b , R ^c , and R ^d , or heterocycloalkyl groups of -C _1-6 alkyl-heterocycloalkyl groups of R ^a , R ^b , R ^c , and R ^d are O, N or Cycloalkyl and heterocycloalkyl groups of R ^a , R ^b , R ^c , and R ^d , having 1, 2, 3, or 4 heteroatoms independently selected from S, and R ^a , R ^b , R ^c , and The heterocycloalkyl group of the —C _1-6 alkyl-heterocycloalkyl group of R ^d may include a double bond, and further R ^a , R ^b , R ^c, R ^d, and cycloalkyl and heterocycloalkyl alkyl, and ^{R a, R b, R c} , and R ^d -C _1-6 alkyl - heterocycloalkyl group in heterocycloalkyl group may contain a group C = O Can;

^{R a, R b, R c} , R ^d, and the alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl group, or ^{R a, R b, R c} , and R ^d in the -C _1-6 alkyl-heterocycloalkyl The heterocycloalkyl group of the alkyl group may be unsubstituted or substituted with 1, 2, 3, or 4 R ¹⁴ substituents, each R ¹⁴ being H, OH, halo, -C _1-6 alkyl, N (CH ₃ ) ₂ , -C _1-6 haloalkyl, C (= 0) CH ₃ , Independently from -C (= 0) OCH ₃ , or -C _1-6 alkyl-OC _1-6 alkyl;

Alternatively, R ^a and R ^b together with the atoms to which they are attached may form a 4- to 12-membered monocyclic or bicyclic ring, but may form a ring optionally containing a heteroatom selected from N, O or S atoms. This ring may contain a double bond;

n is independently at each occurrence an integer of 1, 2, 3 or 4, or a stereoisomer, pharmaceutically acceptable salt thereof, or pharmaceutically acceptable salt of stereoisomer thereof.

34. The compound of any of embodiments 1 to 23, wherein R ^9A is H, —CH ₃ , OH,

으로부터 독립적으로 선택되는 화합물, 또는 이의 입체이성질체, 이의 약제학적으로 허용 가능한 염, 또는 이의 입체이성질체의 약제학적으로 허용 가능한 염.

A compound selected independently from, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof.

35. The compound of embodiment 34, wherein R ^9A is H, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of stereoisomer thereof.

36. The compound of embodiment 34, wherein R ^9A is -CH ₃ , or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of stereoisomer thereof.

37. The compound of embodiment 34, wherein R ^9A is -OH, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of stereoisomer thereof.

인 화합물, 또는 이의 입체이성질체, 이의 약제학적으로 허용 가능한 염, 또는 이의 입체이성질체의 약제학적으로 허용 가능한 염.38. The compound of embodiment 34, wherein R ^9A is

Phosphorus compounds, or stereoisomers thereof, pharmaceutically acceptable salts thereof, or pharmaceutically acceptable salts of stereoisomers thereof.

인 화합물, 또는 이의 입체이성질체, 이의 약제학적으로 허용 가능한 염, 또는 이의 입체이성질체의 약제학적으로 허용 가능한 염.39. The compound of embodiment 34, wherein R ^9A is

Phosphorus compounds, or stereoisomers thereof, pharmaceutically acceptable salts thereof, or pharmaceutically acceptable salts of stereoisomers thereof.

인 화합물, 또는 이의 입체이성질체, 이의 약제학적으로 허용 가능한 염, 또는 이의 입체이성질체의 약제학적으로 허용 가능한 염.40. The compound of embodiment 34, wherein R ^9A is

Phosphorus compounds, or stereoisomers thereof, pharmaceutically acceptable salts thereof, or pharmaceutically acceptable salts of stereoisomers thereof.

인 화합물, 또는 이의 입체이성질체, 이의 약제학적으로 허용 가능한 염, 또는 이의 입체이성질체의 약제학적으로 허용 가능한 염.41. The compound of embodiment 34, wherein R ^9A is

Phosphorus compounds, or stereoisomers thereof, pharmaceutically acceptable salts thereof, or pharmaceutically acceptable salts of stereoisomers thereof.

인 화합물, 또는 이의 입체이성질체, 이의 약제학적으로 허용 가능한 염, 또는 이의 입체이성질체의 약제학적으로 허용 가능한 염.42. The compound of embodiment 34, wherein R ^9A is

Phosphorus compounds, or stereoisomers thereof, pharmaceutically acceptable salts thereof, or pharmaceutically acceptable salts of stereoisomers thereof.

인 화합물, 또는 이의 입체이성질체, 이의 약제학적으로 허용 가능한 염, 또는 이의 입체이성질체의 약제학적으로 허용 가능한 염.43. The compound of embodiment 34, wherein R ^9A is

Phosphorus compounds, or stereoisomers thereof, pharmaceutically acceptable salts thereof, or pharmaceutically acceptable salts of stereoisomers thereof.

인 화합물, 또는 이의 입체이성질체, 이의 약제학적으로 허용 가능한 염, 또는 이의 입체이성질체의 약제학적으로 허용 가능한 염.44. The compound of embodiment 34, wherein R ^9A is

Phosphorus compounds, or stereoisomers thereof, pharmaceutically acceptable salts thereof, or pharmaceutically acceptable salts of stereoisomers thereof.

인 화합물, 또는 이의 입체이성질체, 이의 약제학적으로 허용 가능한 염, 또는 이의 입체이성질체의 약제학적으로 허용 가능한 염.45. The compound of embodiment 34, wherein R ^9A is

Phosphorus compounds, or stereoisomers thereof, pharmaceutically acceptable salts thereof, or pharmaceutically acceptable salts of stereoisomers thereof.

인 화합물, 또는 이의 입체이성질체, 이의 약제학적으로 허용 가능한 염, 또는 이의 입체이성질체의 약제학적으로 허용 가능한 염.46. The compound of embodiment 34, wherein R ^9A is

Phosphorus compounds, or stereoisomers thereof, pharmaceutically acceptable salts thereof, or pharmaceutically acceptable salts of stereoisomers thereof.

인 화합물, 또는 이의 입체이성질체, 이의 약제학적으로 허용 가능한 염, 또는 이의 입체이성질체의 약제학적으로 허용 가능한 염.47. The compound of embodiment 34, wherein R ^9A is

Phosphorus compounds, or stereoisomers thereof, pharmaceutically acceptable salts thereof, or pharmaceutically acceptable salts of stereoisomers thereof.

인 화합물, 또는 이의 입체이성질체, 이의 약제학적으로 허용 가능한 염, 또는 이의 입체이성질체의 약제학적으로 허용 가능한 염.48. The compound of embodiment 34, wherein R ^9A is

Phosphorus compounds, or stereoisomers thereof, pharmaceutically acceptable salts thereof, or pharmaceutically acceptable salts of stereoisomers thereof.

49. Another embodiment of the present invention includes a compound of embodiment 1 or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of stereoisomer thereof, wherein the compound is represented by Formula III

[Formula III];

Has

50. Another embodiment of the present invention includes a compound of any one of embodiments 1 or 49 or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of stereoisomer thereof, wherein the compound is Formula IIIa

 Formula IIIa;

Has

51. The compound of any one of embodiments 1, or 49 to 50, wherein Q is O, -CR ^a R ^b , or NR ^a R ^b , or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a steric thereof Pharmaceutically acceptable salts of the isomers.

52. The compound of embodiment 51, wherein Q is O, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of stereoisomer thereof.

53. The compound of embodiment 52, wherein Q is -CH ₂ , or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of stereoisomer thereof.

54. The compound of embodiment 52, wherein Q is -NR ^a R ^b , or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of stereoisomer thereof.

55. The compound of any one of embodiments 1, or 49 to 54, wherein W is CR ^WA R ^WB , a compound with or without -C═O, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof Pharmaceutically acceptable salts of.

56. The compound of embodiment 55, wherein W is CR ^WA R ^WB , or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of stereoisomer thereof.

57. The compound of embodiment 55, wherein W is absent, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of stereoisomer thereof.

58. The compound of embodiment 1, or any one of 49 to 56, wherein R ^WA and R ^WB are H, -C _1-3 alkyl, -C _1-3 alkenyl, -C _1-3 alkynyl, halo,- OH, or a compound independently selected from -OC _1-3 alkyl, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of its stereoisomer.

59. The compound of embodiment 58, wherein R ^WA and R ^WB are both H, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of stereoisomer thereof.

60. The compound of embodiment 58, wherein R ^WA is -CH ₃ , or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of stereoisomer thereof.

61. The compound of embodiment 58, wherein at least one of R ^WA and R ^WB is H, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of stereoisomer thereof.

62. The compound of embodiment 58, wherein R ^WA is -OH and R ^WB is H, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of stereoisomer thereof.

63. The compound of embodiment 1, or 49 to 62, wherein R ¹ is a haloin compound, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of stereoisomer thereof.

64. The compound of embodiment 63, wherein R ¹ is Cl, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of stereoisomer thereof.

65. The compound of embodiment 1, or 49 to 64, wherein R ³ is H, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of stereoisomer thereof.

66. The compound of embodiment 1, or 49 to 65, wherein R ⁴ is a compound selected from H or —C _1-6 alkyl, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof Pharmaceutically acceptable salts.

67. The compound of embodiment 66, wherein R ⁴ is -CH ₃ , or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of stereoisomer thereof.

68. The compound of embodiment 1, or 49 to 67, wherein R ⁵ is selected from H or —C _1-6 alkyl, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof Pharmaceutically acceptable salts.

69. The compound of embodiment 68, wherein R ⁵ is -CH ₃ , or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of stereoisomer thereof.

70. The compound of any one of embodiments 1 or 49 to 69, wherein R ⁶ is H, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of stereoisomer thereof.

71. The compound of embodiment 1, or 49 to 70, wherein R ⁷ is a compound selected from H or —NR ^a R ^b , or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof Scholarly acceptable salts.

72. The compound of embodiment 71, wherein R ⁷ is H, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of stereoisomer thereof.

73. The compound of embodiment 1, or 49 to 73, wherein R ⁸ is a compound selected from H or —C _1-6 alkyl, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof Pharmaceutically acceptable salts.

74. The compound of embodiment 73, wherein R ⁸ is H, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of stereoisomer thereof.

75. The compound of any one of embodiments 1 or 49 to 70, alternatively R ⁷ and R ⁸ together with the atoms to which they are attached may form a 3- to 12-membered ring, or a stereoisomer thereof , Pharmaceutically acceptable salts thereof, or pharmaceutically acceptable salts of stereoisomers thereof.

76. The compound of any of embodiments 1, 49 to 70, alternatively R ⁷ and R ^9A can form a 3- to 12-membered ring together with the atoms to which they are attached, wherein said ring is at least one A compound optionally containing a double bond, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof.

77. A method according to any one of embodiments 1, 49 to 76, R ⁹ is H, -OH, - (= O ), -C 1 - 6 alkyl, cyano, -C (= O) -C _1-6 Independently selected from alkyl, -C (= 0) -phenyl, -C _1-6 alkyl-O-C _1-6 alkyl, -C _1-6 alkyl- (5 to 10-membered monocyclic or bicyclic heterocycloalkyl) And heterocycloalkyl is a compound which may contain 1, 2, 3 or 4 heteroatoms independently selected from N or O, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof Acceptable salts.

78. The compound of any one of embodiments 1 or 49 to 75, alternatively R ⁹ and R ^9A are a 3- to 12-membered monocyclic or bicyclic ring with Q, W and C to which Q and W bind; To form a ring optionally containing a heteroatom other than Q selected from N, O or S atoms, the ring may contain a double bond, the ring may optionally include a C═O group, and a ring May be optionally substituted with 0, 1, 2, or 3 R ¹¹ substituents;

R ¹¹ is H, halo, -OH, -C _1-6 haloalkyl, -C _1-6 alkyl, -C _1-6 alkyl, -OC _1-6 alkyl, -C (= 0) R ^c , -C (═O) NR ^c R ^d , -NR ^c R ^d , 3-, 12- to 12-membered monocyclic or bicyclic heterocycloalkyl group, the heterocycloalkyl group is 1, 2, 3 independently selected from O, N or S Or having four heteroatoms, the heterocycloalkyl group may comprise a double bond, the heterocycloalkyl group may contain a C═O group, and further the heterocycloalkyl group may be unsubstituted or substituted with one or more -C _1-6 alkyl Or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of its stereoisomer.

79. The compound of any of embodiments 1, 49 to 75 or 77, wherein R ^9A is H, -OH, -C _1-6 alkyl, -C _2-6 alkenyl, -C _2-6 alkynyl, -C _1-6 alkyl, -C (= 0),-(= O), -C (= 0) R ^a , cyano, -C _1-6 alkyl-OC _1-6 alkyl, -OC _1-6 alkyl- OC _1-6 alkyl, -OR ^a , -CSR ^a , -CS (= O) R ^a , -SOR ^a , -NR ^a R ^b , -C (= O) NR ^a R ^b , phenyl, 6-membered to 12-membered aryl or heteroaryl, 5-membered to 12-membered spirocycloalkyl or spiroheterocycloalkyl, or 3-membered to 12-membered cycloalkenyl, 3-membered to 12-membered monocyclic or bicyclic cycloalkyl, or Independently selected from 3- to 12-membered monocyclic or bicyclic heterocycloalkyl groups, heteroaryl and heterocycloalkyl groups have 1, 2, 3 or 4 heteroatoms independently selected from O, N or S, and cycloalkyl And heterocycloalkyl groups may contain double bonds, and cycloalkyl and heterocycloalkyl groups may include C═O groups. And further, the heterocycloalkyl group may comprise S═O or SO ₂ ;

The aryl, heteroaryl, cycloalkyl, and heterocycloalkyl groups of the R ^9A substituent are unsubstituted or substituted with 1, 2, 3 or 4 R ¹⁰ substituents independently selected from -NR ^c R ^d , or -C _1-6 alkyl. Can be;

C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, and —OC _1-6 alkyl of any one of R ^9A and R ¹⁰ substituents may be unsubstituted or substituted with OH, halo,-(= O) , -OC _1-6 alkyl, -C _1-6 alkyl, -NR ^a R ^b , -SiR ^a R ^b R ^c , 6- to 12-membered aryl or heteroaryl, 3- to 12-membered monocyclic or Substituted by 1, 2 or 3 R ¹² substituents independently selected from bicyclic heterocycloalkyl groups, the heteroaryl or heterocycloalkyl group having 1, 2, 3 or 4 heteroatoms independently selected from O, N or S Wherein the heterocycloalkyl group may comprise a C═O group, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of its stereoisomer.

80. The compound of any of embodiments 1, 49 to 76, wherein R ⁹ is H, —OH, —CH ₃ , —CH ₂ CH ₃ , —C (═O) CH ₃ ,

,

, 또는

으로부터 독립적으로 선택되는 화합물, 또는 이의 입체이성질체, 이의 약제학적으로 허용 가능한 염, 또는 이의 입체이성질체의 약제학적으로 허용 가능한 염.-CH ₂ C (= 0) OCH ₂ CH ₃ ,

,

, or

A compound selected independently from, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof.

81. The compound of embodiment 80, wherein R ⁹ is H, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of stereoisomer thereof.

82. The compound of embodiment 80, wherein R ⁹ is -CH ₃ , or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of stereoisomer thereof.

83. The compound of any one of embodiments 1, 49-75, or 77-80, wherein R ^9A is H, -OH, -CH ₃ , -CH ₂ CH ₃ , -OCH ₂ C (= 0) OCH ₂ CH ₃ ,

으로부터 독립적으로 선택되는 화합물, 또는 이의 입체이성질체, 이의 약제학적으로 허용 가능한 염, 또는 이의 입체이성질체의 약제학적으로 허용 가능한 염.or

A compound selected independently from, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof.

84. The compound of embodiment 83, wherein R ^9A is H, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of stereoisomer thereof.

85. The compound of embodiment 83, wherein R ^9A is —C _1-6 alkyl, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of stereoisomer thereof.

86. The compound of embodiment 83, wherein R ^9A is -CH ₃ , or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of stereoisomer thereof.

인 화합물, 또는 이의 입체이성질체, 이의 약제학적으로 허용 가능한 염, 또는 이의 입체이성질체의 약제학적으로 허용 가능한 염.87. The compound of embodiment 83, wherein R ^9A is

Phosphorus compounds, or stereoisomers thereof, pharmaceutically acceptable salts thereof, or pharmaceutically acceptable salts of stereoisomers thereof.

88. The compound of any of embodiments 1, 49 to 75 and 78, alternatively R ⁹ and R ^9A together with the atoms to which they are attached form a 5- to 12-membered monocyclic or bicyclic ring, wherein N, O Or a ring optionally containing a heteroatom other than Q selected from S atoms, and further, the 5 to 12 membered ring may contain a double bond, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. Or pharmaceutically acceptable salts of stereoisomers thereof.

를 형성하는 화합물, 또는 이의 입체이성질체, 이의 약제학적으로 허용 가능한 염, 또는 이의 입체이성질체의 약제학적으로 허용 가능한 염.89. The compound of embodiment 88, wherein R ⁹ and R ^9A are combined with Q, W and C to which Q and W bind

Or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of its stereoisomer.

90. Another embodiment of the present invention includes a compound, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof, wherein the compound is

로부터 선택된 구조를 갖는다.

It has a structure selected from.

91. Another embodiment of the present invention includes a compound, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof, wherein the compound is

or

It has a structure selected from.

92. A compound of embodiment 91 or a pharmaceutically acceptable salt thereof.

93. Another embodiment of the present invention includes a pharmaceutical composition comprising a compound of any one of embodiments 1 to 92 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.

94. Another embodiment of the invention includes a method of treating cancer, the method comprising a method for treating a patient in need thereof with a therapeutically effective amount of a compound of any one of embodiments 1 to 92 or a pharmaceutically acceptable salt thereof. Administering.

95. The method of embodiment 94, wherein the cancer is a hematologic malignancy.

96. The cancer cell of embodiment 94, wherein the cancer consists of breast cancer, colon cancer, skin cancer, melanoma, ovarian cancer, kidney cancer, lung cancer, non-small cell lung cancer, lymphoma, non-Hodgkin's lymphoma, myeloma, multiple myeloma, leukemia, and acute myeloid leukemia. Selected from the group.

97. The method of embodiment 94, wherein the cancer is multiple myeloma.

98. The method of embodiment 94, further comprising administering a therapeutically effective amount of a pharmaceutically active additional compound to the patient in need thereof.

99. The method of embodiment 98, wherein the further pharmaceutically active compound is carfilzomib.

100. The method of embodiment 98, wherein the further pharmaceutically active compound is Venetoclarks.

101. The method of embodiment 98, wherein the further pharmaceutically active compound is cytarabine.

102. Another embodiment of the present invention includes the use of a compound according to any one of embodiments 1 to 92 in treating cancer in a subject.

103. Another embodiment of the present invention includes a compound according to any one of embodiments 1 to 92 in the manufacture of a medicament for the treatment of cancer.

104. The compound of embodiment 103, wherein the cancer is a hematologic malignancy.

105. The cancer cell of embodiment 102, wherein the cancer consists of breast cancer, colon cancer, skin cancer, melanoma, ovarian cancer, kidney cancer, lung cancer, non-small cell lung cancer, lymphoma, non-Hodgkin's lymphoma, myeloma, multiple myeloma, leukemia, and acute myeloid leukemia Compound selected from the group.

106. The compound of embodiment 102, wherein the cancer is multiple myeloma.

107. The compound of embodiment 102, wherein the cancer is acute myeloid leukemia.

108. The compound of embodiment 102, wherein the cancer is non-Hodgkin's lymphoma.

Another embodiment of the present invention relates to a method for inhibiting myeloid cell leukemia 1 protein (Mcl-1) of a cell, the method comprising: Contacting the cell with a compound of the. In one embodiment, the contacting step is in vitro . In another embodiment, the contacting step is in vivo . In one embodiment, contacting comprises administering the compound to the subject. In one embodiment, the contacting step is in vitro . In another embodiment, the contacting step is in vivo . In one embodiment, contacting comprises administering the compound to the subject. In one embodiment, the administering step is oral administration, parenteral administration, administration by injection, administration by inhalation, transdermal or transmucosal administration. In one embodiment, the subject suffers from cancer.

One embodiment of the present invention relates to a method for treating cancer, the method comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutical composition comprising a compound of formula (I), in combination with any of the embodiments described above or below, Or administering a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient to a patient in need thereof. In one embodiment, the cancer is a hematologic malignancy. In one embodiment, the cancer is selected from the group consisting of breast cancer, colon cancer, skin cancer, melanoma, ovarian cancer, kidney cancer, lung cancer, non-small cell lung cancer, lymphoma, non-Hodgkin's lymphoma, myeloma, multiple myeloma, leukemia and acute myeloid leukemia do. In one embodiment, the cancer is multiple myeloma. In another embodiment, the method further comprises administering to the patient in need thereof a therapeutically effective amount of at least one additional compound that is pharmaceutically active. In one embodiment, the additional pharmaceutically active compound is carfilzomib, in combination with any of the preceding embodiments.

The methods provided herein include the manufacture and use of pharmaceutical compositions comprising one or more of the compounds provided herein. Pharmaceutical compositions themselves are also included.

In some claims, the compounds provided herein may include one or more acidic functional groups, and thus may form pharmaceutically acceptable salts with pharmaceutically acceptable bases. The term “pharmaceutically acceptable salts” in these cases refers to the relatively nontoxic inorganic and organic base addition salts of the compounds provided herein. These salts can likewise be prepared in situ during the final isolation and purification of the compound, or purified compounds in free acid form with suitable bases such as hydroxides, carbonates, or bicarbonates of pharmaceutically acceptable metal cations, ammonia, or pharmaceuticals. It can be prepared by separately reacting with an academically acceptable organic primary, secondary, or tertiary amine. Representative alkali or alkaline earth metal salts include lithium, sodium, potassium, calcium, magnesium and aluminum salts and the like. Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like (see, eg, Berge et al., Supra).

Wetting agents, emulsifiers and lubricants such as sodium lauryl sulfate and magnesium stearate, as well as colorants, mold release agents, coatings, sweeteners, flavoring and fragrances, preservatives and antioxidants

Examples of pharmaceutically acceptable antioxidants include: (1) water soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfate, sodium sulfite and the like; (2) oily antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propylgallate, alpha-tocopherol and the like; And (3) metal chelating agents such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid and the like.

Pharmaceutical compositions may also include adjuvants such as preservatives, wetting agents, emulsifiers and dispersants. Prevention of the action of microorganisms can be ensured by the inclusion of various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol sorbic acid and the like. It may also be desirable to include isotonicity modifiers such as sugars and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents that delay absorption such as aluminum monostearate and gelatin.

In some cases, it may be desirable to slow the absorption of a compound from subcutaneous or intramuscular injection, in order to prolong the effects of one or more compounds provided herein. For example, delayed absorption of the parentally administered compound can be achieved by dissolving or suspending the compound in an oil vehicle.

Compounds of the invention are administered to a patient in a therapeutically effective amount. The compound may be administered alone or as part of a pharmaceutically acceptable composition or formulation. In addition, the compounds or compositions may be administered all at once (eg bolus injection), multiple times (eg sequential administration of tablets), or delivered substantially uniformly over a period of time (eg transdermal delivery). ). The dose of the compound or composition may vary over time. All combinations, methods of delivery and order of administration are contemplated.

Compounds of the invention and, in some claims, further pharmaceutically active compounds can be administered orally, rectally, parenterally (eg, intravenously, intramuscularly or subcutaneously) to patients, intracranially, It may be administered intravaginally, intraperitoneally, intraperitoneally, topically (eg, powder, ointment or drip) or as an oral or nasal spray. All methods used by those skilled in the art for administering pharmaceutically active agents are contemplated.

As is well known to those skilled in the art, compositions prepared as described herein can be administered in various forms depending on the disorder to be treated, the age, condition and weight of the patient. For example, when the compositions are administered orally, they may be formulated as tablets, capsules, granules, powders or syrups; Or for parenteral administration, they may be formulated as injections (intravenous, intramuscular or subcutaneous), as instillation preparations or as suppositories. For application by the ocular mucosal route, they can be formulated as eye drops or eye ointments. These formulations may be prepared by conventional means in combination with the methods described herein, and if desired, the active ingredient may be any conventional additives or excipients such as binders, disintegrants, lubricants, correctors, solubilizers, suspension aids, It can be mixed with emulsifiers or coatings.

Formulations suitable for oral administration may be in the form of capsules (eg gelatin capsules), sachets, pills, tablets, lozenges (using flavored bases, usually sucrose and acacia or tragacanth), powders, troches, granules As a solution or suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as a spice (using an inert substrate such as gelatin and glycerin or sucrose and acacia) and And / or mouthwashes, etc., each containing a predetermined amount of a compound provided herein as an active ingredient. The composition can also be administered as a bolus, a paste, or a paste. Oral compositions generally include an inert diluent or an edible carrier.

Pharmaceutically suitable binders and / or adjuvant materials may be included as part of the oral composition. In solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules, etc.), the active ingredient may be added to one or more pharmaceutically acceptable carriers such as sodium citrate or dicalcium phosphate and / or any It may be mixed with those mentioned: (1) fillers or extenders such as starch, cyclodextrin, lactose, sucrose, saccharin, glucose, mannitol and / or silicic acid; (2) binders such as carboxymethylcellulose, microcrystalline cellulose, tragacanth gum, alginate, gelatin, polyvinylpyrrolidone, sucrose and / or acacia; (3) humectants, such as glycerol; (4) disintegrants such as agar-agar, calcium carbonate, potatoes, corn or tapioca starch, alginic acid, primogel, certain silicates and sodium carbonate; (5) solution buffering agents such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as acetyl alcohol and glycerol monostearate; (8) absorbents such as kaolin and bentonite clay; (9) lubricants, such as talc, calcium stearate, magnesium stearate, sterot, solid polyethylene glycols, sodium lauryl sulfate and mixtures thereof; (10) glidants such as colloidal silicon dioxide; (11) colorants; And (12) flavoring agents such as peppermint, methyl salicylate or orange flavor. In the case of capsules, tablets and pills, the pharmaceutical composition may also comprise a buffer. Solid compositions of a similar type may also be used as fillers in soft and hard filled gelatin capsules using excipients such as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may contain binders (eg gelatin or hydroxypropylmethyl cellulose), lubricants, inert diluents, preservatives, disintegrants (eg sodium glycolate starch or crosslinked carboxymethyl cellulose), surface active agents or dispersants It can be prepared using. Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

Tablets and other solid dosage forms such as dragees, capsules, pills and granules may optionally be scored or prepared by coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulation art. They also vary in proportion to provide the desired release profile, other polymeric substrates, liposomes, microspheres and / or nanoparticles, for example slow or controlled in tablets or formulations using hydroxypropylmethyl cellulose. It may be formulated to provide release of the active ingredient. They can be sterilized, for example, by filtration through a bacteria-retaining filter or by incorporating the sterilant in the form of a sterile solid composition that can be dissolved in sterile water or in some other sterile injectable medium immediately before use. have. These compositions may also optionally contain opacifying agents and may be compositions which release only the active ingredient (s), or preferentially in certain parts of the gastrointestinal tract, optionally in a delayed manner. Examples of incorporation compositions that can be used include polymeric substances and waxes. The active ingredient may also be in microencapsulated form with one or more of the excipients described above, where appropriate.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, liquid dosage forms include inert diluents commonly used in the art, such as water or other solvents, solubilizers, and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl Alcohols, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofuryl alcohol, polyethylene glycol And fatty acid esters of sorbitan, and mixtures thereof.

In addition to inert diluents, oral compositions may also include auxiliaries such as wetting agents, emulsifiers and suspending agents, sweetening agents, flavoring agents, coloring agents, fragrances and preservatives.

In addition to the active compound (s), the suspension may contain suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and Tragacanth and mixtures thereof.

Pharmaceutical compositions suitable for parenteral administration include one or more pharmaceutically acceptable sterile aqueous solutions which may contain antioxidants, buffers, fungicides, suspensions or thickeners or solutes that provide a formulation that is isotonic with the blood of the intended recipient. Or one or more compounds provided herein in combination with non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders that can be reconstituted into sterile injectable solutions or dispersions immediately prior to use.

In one claim, the IV formulation consists of a composition containing as a buffered or unbuffered solution of hydroxypropyl beta cyclodextrin having a pH range of 8 to 10. IV formulations may be formulated as sterile solutions prepared for injection, sterile solutions prepared for dilution with IV mixtures or sterile solids for reconstitution. In IV formulations the API may be present as free acid / base or as an in situ salt.

Examples of suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions provided herein include water for injection (eg, sterile water for injection), bacteriostatic water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, such as liquids). Polyethylene glycols, etc.), sterile buffers (such as citrate buffers), and suitable mixtures thereof, vegetable oils such as olive oil, injectable organic esters such as ethyl oleate and Cremophor EL (tradename) BASF, Furney). In all cases, the composition must be sterile and fluid to the extent that easy syringability exists. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

The composition must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. Prevention of microbial action can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, and sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by the inclusion of agents in the composition which delay absorption, such as aluminum monostearate and gelatin.

Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in the appropriate solvent with one or a combination of ingredients enumerated above, if necessary, followed by sterile filtration. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle which contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the method of preparation is lyophilization (freeze-drying), which obtains the powder of the active ingredient plus any additional desired components from the previous sterile filtered solution.

Injectable depot forms can be prepared by forming microcapsule or nanocapsule substrates of the compounds provided herein with biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer and the nature of the particular polymer used, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes, microcapsules or nanoemulsions suitable for body tissue.

For administration by inhalation, the compound may be delivered in the form of an aerosol spray from a pressurized vessel or dispenser or nebulizer containing a suitable propellant (eg a gas such as carbon dioxide). Such methods include those described in US Pat. No. 6,468,798. In addition, intranasal delivery is particularly described in Hamajima et al. Clin. Immunol. Immunopathol ., 88 (2), 205-10 (1998). Liposomes (eg, as described in US Pat. No. 6,472,375, which is incorporated by reference in its entirety), microencapsulation and nanoencapsulation may also be used. Biodegradable targetable microparticle delivery systems or biodegradable targetable nanoparticle delivery systems may also be used (eg, as described in US Pat. No. 6,471,996, which is incorporated by reference in its entirety).

Systemic administration of the therapeutic compounds described herein may also be by transmucosal or transdermal means. Dosage forms for topical or transdermal administration of a compound provided herein include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. The active ingredient can be mixed under sterile conditions with a pharmaceutically acceptable carrier and with any preservatives, buffers or propellants that may be required. For transmucosal or transdermal administration, penetrants suitable for the barrier to be penetrated are used in this formulation. Such penetrants are generally known in the art and include, for example, detergents, bile salts and fusidic acid derivatives for transmucosal administration. Transmucosal administration can be achieved through the use of nasal sprays or suppositories. For transdermal administration, the active compounds are formulated into ointments, salbs, gels or creams as is generally known in the art.

Ointments, pastes, creams and gels may be used in addition to one or more compounds provided herein, including excipients such as animal and vegetable fats, oils, waxes, paraffins, starches, tragacanths, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acids , Talc and zinc oxide or mixtures thereof.

Powders and sprays may contain, in addition to the compounds provided herein, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate and polyamide powder, or mixtures of these materials. Sprays may additionally contain customary propellants such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons such as butane and propane.

The compounds provided herein can be administered by aerosol. This is accomplished by preparing an aqueous aerosol, liposome formulation or solid particles containing a compound or composition provided herein. Non-aqueous (eg fluorocarbon propellant) suspensions could be used. In some claims, a sonic nebulizer is used because sonic nebulizer minimizes exposure of the formulation to shear, which can result in degradation of the compound.

Usually, aqueous aerosols can be prepared by formulating an aqueous solution or suspension of the formulation with conventional pharmaceutically acceptable carriers and stabilizers. Carriers and stabilizers vary depending on the requirements of the particular composition, but include nonionic surfactants (TWEEN ^® (polysorbate), PLURONIC ^® (poloxamer), sorbitan esters, lecithin, CREMOPHOR® (polyethoxylate)), drugs Academicly acceptable cosolvents (e.g. polyethylene glycol), harmless proteins such as serum albumin, sorbitan esters, oleic acid, lecithin, amino acids (e.g. glycine), buffers, salts, sugars or sugar alcohols. Aerosols are generally prepared from isotonic solutions.

Transdermal patches have the added advantage of providing controlled delivery of a compound provided herein to the body. Such dosage forms can be made by dissolving or dispersing the agent in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate of this flow can be controlled by providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.

Pharmaceutical compositions can also be prepared in the form of suppositories or retention enemas for rectal and / or vaginal delivery. Formulations provided as suppositories include one or more compounds provided herein, for example, cocoa butter, glycerides, polyethylene glycols, suppositories, which are solid at room temperature but are liquid at body temperature and thus melt in the rectum or vaginal cavity and release the active agent. It can be prepared by mixing with one or more suitable non-irritating excipients or carriers, including waxes or salicylates. Formulations suitable for vaginal administration also include pessary, tampon, cream, gel, paste, foam or spray formulations containing carriers as known in the art.

In one claim, the therapeutic compound is prepared with a carrier, such as a controlled release formulation, that will protect the therapeutic compound from rapid removal from the body, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Such formulations may be prepared using standard techniques or may be obtained commercially (eg, Alza Corporation and Nova Pharmaceuticals, Inc.). Liposomal suspensions (including liposomes targeted to selected cells by monoclonal antibodies to cellular antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in US Pat. No. 4,522,811, which is incorporated by reference in its entirety for all purposes.

Compounds of the invention are used in the treatment of diseases, disorders or symptoms mediated by Mcl-1 inhibition. Examples of diseases, disorders or symptoms mediated by Mcl-1 inhibition include, but are not limited to, cancer. Non-limiting examples of cancer include breast cancer, colon cancer, skin cancer, melanoma, ovarian cancer, kidney cancer, lung cancer, non-small cell lung cancer, lymphoma, non-Hodgkin's lymphoma, myeloma, multiple myeloma, leukemia and acute myeloid leukemia.

The cancer may be carcinoma (derived from the outer layers of skin and lining, such as breast, kidney, lung, skin cells); Sarcomas (from connective tissue such as bone, muscle, cartilage and blood vessels), and hematologic malignancies (eg, lymphoma and leukemia from blood or blood-forming organs such as the spleen, lymph nodes and bone marrow) have. Cancer cells can include, for example, tumor cells, neoplastic cells, malignant tumor cells, metastatic cells and hyperplasia cells.

In the claims, the disease, disorder or condition is a hyperproliferative disorder such as lymphoma, leukemia, carcinoma (eg kidney, breast, lung, skin), multiple myeloma or sarcoma. In one claim, the leukemia is acute myeloid leukemia. In one claim, the hyperproliferative disorder is a relapsed or refractory cancer.

The actual dosage level of the active ingredient in the pharmaceutical compositions provided herein will vary so as to obtain an amount of active ingredient effective to achieve the desired therapeutic response, composition, and mode of administration of the particular patient without becoming toxic to the patient. Can be.

The specific dosage and dosage range depends on a number of factors including the patient's needs, the severity of the condition or disease to be treated, the pharmacokinetic characteristics of the compound (s) used and the route of administration. In some claims, the compositions provided herein may be provided in an aqueous solution for parenteral administration containing, among other materials, from about 0.1 to 10% w / v of the compounds disclosed herein. Typical dosage ranges may include from about 0.01 to about 50 mg / kg body weight per day, given in 1 to 4 divided doses. Each divided dose may contain the same or different compound. The dosage will be a therapeutically effective amount depending on several factors including the patient's general health and the formulation and route of administration of the selected compound (s).

Dosage forms or compositions can be prepared that contain a compound as described herein in the range of 0.005% to 100%, with the remainder consisting of a nontoxic carrier. Methods of making these compositions are known to those skilled in the art. The contemplated compositions may contain from about 0.001% to 100% active ingredient, in one claim from about 0.1% to about 95%, and in still another claim from about 75% to about 85%. The dosage will vary depending on the patient's symptoms, age and weight, the nature and severity of the disorder to be treated or prevented, the route of administration and the form of the drug, but in general, a daily dosage of about 0.01 to about 3,000 mg of the compound is adult human patients Recommended for, it may be administered in a single dose or in divided doses. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound that produces a therapeutic effect.

The pharmaceutical composition may be administered at one time or may be divided into a number of smaller doses to be administered at time intervals. It is understood that the exact dosage and duration of treatment are a function of the disease to be treated and can be determined empirically using known test protocols or by inference from in vivo or in vitro test data. It will be noted that concentration and dosage values may also vary depending on the severity of the condition to be alleviated. For any particular patient, the particular dosage regimen should be adjusted over time according to individual needs and by the professional judgment of the person administering or supervising the composition, and the concentration ranges presented herein are merely illustrative. It is further understood that it is not intended to limit the scope of the claimed composition or its practice.

The exact time of administration and / or amount of composition that will yield the most effective results in terms of therapeutic efficacy in a given patient will depend on the activity, pharmacokinetics and biocompatibility of the particular compound, the patient's physiological conditions (age, sex, disease type and stage, general Physical condition, including responsiveness to a given dosage, and type of drug), route of administration, and the like. However, the guidelines can be used as a basis for fine-tuning treatment, for example to determine the optimal dosing time and / or dosage, which is to monitor the patient and to adjust the dosage and / or timing. You won't need more than your routine routine.

The compounds of the present invention can be administered alone or in combination with other compounds of the present invention, or other pharmaceutically active compounds or agents. Other pharmaceutically active compounds / agents may be intended to treat the same disease or condition as the compounds of the present invention or different diseases or conditions. If the patient is receiving or is receiving multiple pharmaceutically active compounds or agents, the compounds may be administered simultaneously or sequentially.

The compounds of the present invention, or pharmaceutically acceptable salts thereof, may be used in combination with one or more pharmaceutically active additional compounds / agents.

One or more pharmaceutically active additional compounds or agents may be separated (eg, sequentially) from the compound of formula (I) as part of a multi-dose regimen, eg, one or more compounds of formula I (any subgen or Administration on a different overlapping schedule than that of the particular compound). In other claims, one or more additional compounds / agents may be part of a single dosage form mixed with a compound of formula (I) in a single composition. In another claim, one or more additional compounds / agents are administered at about the same time that one or more compounds of Formula (I) are administered, eg, administration of one or more compounds of Formula (including any subgen or specific compound thereof) And as separate doses that are administered simultaneously. Both the compound of formula (I) and one or more additional compounds / agents may be present at dosage levels of about 1 to 100%, and more preferably about 5 to 95% of the dosage normally administered in a monotherapy regimen.

In certain claims, further pharmaceutically active compounds / agents are compounds or agents that can be used to treat cancer. For example, additional compounds / agents that are pharmaceutically active may be selected from anti-neoplastic, anti-angiogenic, chemotherapeutic and peptide cancer therapeutics. In another claim, the anti-neoplastic agent is selected from antibiotic-type agents, alkylating agents, anti-metabolic agents, hormones, immunological agents, interferon-type agents, kinase inhibitors, proteasome inhibitors and combinations thereof. It is noted that further pharmaceutically active compounds / agents may be traditional small organic chemical molecules or may be macromolecules such as proteins, antibodies, peptibodies, DNA, RNA or fragments of such macromolecules.

Examples of pharmaceutically active additional compounds / agents that can be used in the treatment of cancer and can be used in combination with one or more compounds of the invention include: acemanan; Aclarubicin; Aldesleukin; Alitretinoin; Amifostine; Amrubicin; Amsacrine; Anagrelide; Arglabin; Arsenic trioxide; BAM 002 (Novelos); Bicalutamide; Broxuridine; Selmoleukin; Setlorellix; Cladribine; Clotrimazole; Cytarabine; DA 3030 from Dong-A; Daclizumab; Denyleukin diftitox; Deslorelin; Dilazef; Docosanol; Docecalciferol; Doxyfluidine; Bromocriptine; Cytarabine; HIT Diclofenac; Interferon alpha; Tretinoin; Edelfosine; Edrecolomab; Eflornithine; Emitepur; Epirubicin; Epoetin beta; Etoposide phosphate; Excisulind; Padrosol; Finasteride; Fludarabine phosphate; Pomestan; Potemustine; Gallium nitrate; Gemtuzumab jogamycin; A gimeracil / otheracil / tegapur combination; Glycopine; Goserelin; Heptaplatin; Human chorionic gonadotropin; Human fetal alpha fetal protein; Ibandronic acid; Interferon alpha; Interferon alpha natural; Interferon alpha-2; Interferon alfa-2a; Interferon alpha-2b; Interferon alpha-N1; Interferon alpha-n3; Interferon alfacon-1; Interferon alpha natural; Interferon beta; Interferon beta-1a; Interferon beta-1b; Interferon gamma natural; Interferon gamma-1a; Interferon gamma-1b; Interleukin-1 beta; Iobenguan; Irsoglandin; Lanreotide; LC 9018 (Yakult); Leflunomide; Renograstim; Lentinan sulfate; Letrozole; Leukocyte alpha interferon; Leuprorelin; Levamizol + fluorouracil; Liarosol; Lovaplatin; Rodidamine; Lovastatin; Masoprocol; Merarsoprol; Metoclopramide; Mifepristone; Miltefosine; Myrimos team; Mismatched double stranded RNA; Mitoguazone; Mitolactol; Mitoxantrone; Molgramos team; Naparelin; Naloxone + pentazosin; Nartograstim; Nedaplatin; Nilutamide; Noscarpine; Novel erythroid stimulating proteins; NSC 631570 Octreotide; Oprelvekin; Ostherone; Paclitaxel; Pamidronic acid; Peginterferon alpha-2b; 243 rimethyl polysulfate sodium; Pentostatin; Fishvanyl; Pyrarubicin; Rabbit antithyroid polyclonal antibody; Polyethylene glycol interferon alfa-2a; Porphymer sodium; Raltitrexed; Rasburicaze; Rhenium Re 186 ethedronate; RII retinamide; Lomurtide; Samarium (153 Sm) residronam; Sargramos team; Sizofuran; Small aliphatic acid; Sonermin; Strontium-89 chloride; Suramin; Tasornermine; Tazarotene; Tegapur; Temophorpine; Teniposide; Tetrachlorodecaoxide; Timalphacin; Tyrotropin alpha; Toremifene; Tocitumomab-iodine 131; Threosulfane; Tretinoin; Trirostane; Trimetrexate; Tryptorelin; Trametinib; Tumor necrosis factor alpha natural; Juvenimex; Bladder cancer vaccine; Maruyama vaccine; Melanoma lysate vaccine; Varubicin; Venetoclarks; Berteporphine; Birulyzin; Ginostatin stymalamer; Abarelix; AE 941 (Aeterna); Ambamustine; Antisense oligonucleotides; bcl-2 (Genta); APC 8015 (Dendreon); Dexaminoglutettimide; Diajikuon; EL 532 (Elan); EM 800 (Endorecherche); Enyluracil; Ethanidazol; Fenretinide; Gallocitabine; Gastrin 17 immunogen; HLA-B7 gene therapy (Vical); Granulocyte macrophage colony stimulating factor; Histamine dihydrochloride; Ibritumomab thiuxetane; Ilostat; IM 862 (Cytran); Interleukin-2; Iproxyfen; LDI 200 (Milkhaus); Laredith team; Lintuzumab; CA 125 monoclonal antibody ((Mab (Biomira); Cancer Mab (Japan Pharmaceutical Development); HER-2 and Fc Mab (Medarex); Genotype 105AD7 Mab (CRC Technology); Genotype CEA Mab (Trilex); LYM-1-iodine 131 Mab (Techniclone); polymorphic epithelial mucin-yttrium 90 Mab (Antisoma); marimastat; menogaryl; mitumomab; motexapine gadolinium; MX 6 (Galderma); nolatrexed; P 30 protein; pegbisomant; Porphyromycin; prinostat; RL 0903 (Shire); rubithecane; satraplatin, sodium petyl acetate; saparfosinic acid; SRL 172 (SR Pharma); SU 5416 (SUGEN); TA 077 (Tanabe); tetrathio Molybdate; thaliblastine; thrombopoietin; ethyl thiofurfurin tin; tyrapazamine; cancer vaccine (Biomira); melanoma vaccine; melanoma tumor cell lysate vaccine; viral melanoma cell lysate vaccine; Vals Podal; Fluorouracil; 5-Fluorouracil; 244rimethyla; Imatinib; Altretamine; Dibrain; cyclophosphamine; decarazine; irinotecan; mitomycin; mitoxane; topotecan; vinorelbine; 244rimethyla; mitram; imiquimod; alemtuzumab; exemestane; bevacizumab; cetuxima Mab; Azacytidine; Cloparabine; Decitabine; Desatibini; Dexrazoic acid; Docetaxel; Epirubicin; Oxaliplatin; Erlotinib; Raloxifene; Fulvestant; Letrozole; Gefitinib; Gemtuzumab; Trab Stuzumab; gefitinib; ixabepilone; lapatinib; lenalidomide; aminolevulinic acid; temozolomide; ellarabine; sorafenib; nilotinib; pegaspagase; pemetrexed; rituximab Dasatanib; thalideramide; bexarotene; temsirolimus; bortezomib; 244rilamlam; offrozomib; borinostat; capecitabine; zoledronic acid; anastrozole; sunitinib; aprepi Tant and ellarabine, or a pharmaceutically acceptable salt thereof.

Pharmaceutically active additional compounds / agents that can be used in the treatment of cancer and used in combination with one or more compounds of the invention include: epoetin alfa; Darbepoetin alfa; Panitumumab; Pegfilgrastim; Palipermine; Filgrastim; Denosumab; Ancess team; AMG 102; AMG 386; AMG 479; AMG 655; AMG 745; AMG 951; And AMG 706, or a pharmaceutically acceptable salt thereof.

In certain claims, the compositions provided herein are administered jointly with a chemotherapeutic agent. Suitable chemotherapeutic agents include natural products such as vinca alkaloids (eg vinblastine, vincristine, and vinorelbine), paclitaxel, epidipodophyllotoxins (eg etoposide and teniposide). Antibiotics (eg, dactinomycin (actinomycin D), daunorubicin, doxorubicin, and idarubicin), anthracyclines, mitoxantrone, bleomycin, plicamycin (mithramycin), mitomycin, Enzymes (e.g., L-asparaginases that systemically metabolize L-asparagine and deprive cells not capable of synthesizing their own asparagine), antiplatelet agents, antiproliferative / antimitotic alkylating agents, for example Nitrogen mustards (eg mechloretamine, cyclophosphamide and analogues, melphalan, and chlorambucil), ethyleneimine and methylmelamine (eg hexamethylmelamine and thiotepa), CDK inhibitors ( For example, Celicicclip, UCN-01, P1446A-05, PD-0332991, Dinaciclip, P27-00, AT-7519, RGB286638, and SCH727965), Alkyl sulfonic acid (e.g., busulfan), Nitroso Urea (eg, carmustine (BCNU) and analogs, and streptozosin), tragenes-dacarbazinin (DTIC), antiproliferative / antimitotic anti-metabolites, eg folic acid analogs (eg, Methotrexate), pyridine analogs (eg fluorouracil, phloxuridine, and cytarabine), purine analogs and related inhibitors (eg mercaptopurine, thioguanine, pentostatin and 2-chlorodeoxyadenosine) , Aromatase inhibitors (eg anastrozole, exemestane, and letrozole), and platinum coordination complexes (eg cisplatin and carboplatin), procarbazine, hydroxyurea, mitotan, Aminoglutetimides, histone deacetylase (HDAC) inhibitors (eg, tricosta Chitin, sodium butyrate, apicidan, suveroyl anilide hydroamic acid, vorinostat, LBH 589, romidipsin, ACY-1215, and panobinostat), mTor inhibitors (e.g., temsirolimus, everolimus, Lidaporolimus, and sirolimus), KSP (Eg5) inhibitors (eg Array 520), DNA binders (eg Zalypsis), PI3K delta inhibitors (eg GS-1101 and TGR- 1202), PI3K delta and gamma inhibitors (eg CAL-130), multi-kinase inhibitors (eg TG02 and sorafenib), hormones (eg estrogens) and hormone agonists such as corpus luteum Hormone releasing hormone (LHRH) agonists (eg goserelin, leuprolide and tryptorelin), BAFF-neutralizing antibodies (eg LY2127399), IKK inhibitors, p38MAPK inhibitors, anti-IL-6 (eg For example, CNTO328), telomerase inhibitors (eg GRN 163L), Aurora kinase inhibitors (eg MLN8237), cell surface Monoclonal antibodies (eg, anti-CD38 (HUMAX-CD38), anti-CS1 (eg, erotuzumab), KRAS inhibitors including covalent inhibitors of KRAS G12C, MEK inhibitors including trametinib, HSP90 Inhibitors (eg 17 AAG and KOS 953), P13K / Akt inhibitors (eg Periposine), Akt inhibitors (eg GSK-2141795), PKC inhibitors (eg Enzastaurine), FTI (eg Zarnestra ™), anti-CD138 (eg BT062), Torc1 / 2 specific kinase inhibitors (eg INK128), kinase inhibitors (eg GS-1101), ER / UPR targeting agents (eg MKC-3946), cFMS inhibitors (eg ARRY-382), JAK1 / 2 inhibitors (eg CYT387), PARP inhibitors (eg Olaparip and Bellifalip ( ABT-888)), and BCL-2 antagonists. Other chemotherapeutic agents may include mechloretamine, camptothecin, ifosfamide, tamoxifen, raloxifene, gemcitabine, nabelbin, sorafenib, or any analog or derivative of any of the foregoing.

The compounds of the present invention can also be used in combination with radiation therapy, hormonal therapy, surgery and immunotherapy, which are well known to those skilled in the art.

In certain claims, the pharmaceutical compositions provided herein are administered in combination with a steroid. Suitable steroids include 21-acetoxypregnenolone, alclomethasone, alzestone, amcinonide, beclomethasone, betamethasone, budesonide, chloroprednisone, clobetasol, clocortolone, cloprednol, corticosterone , Cortisone, cortibazole, deplazacoat, desonide, desoxymethasone, dexamethasone, diploson, diflucortolone, difufredate, enoxolone, fluazacoat, fluchloronide, flumethasone, flu Nisolide, fluorinolone acetonide, fluorinoneide, fluorocortin butyl, fluorocortolone, fluorometholone, fluperolone acetate, fluprednide acetate, fluprednisolone, flulandrenolide, fluticasone propio Nate, Formocortal, Halsinide, Halobetasol Propionate, Halomethasone, Hydrocortisone, Loteprednol Ethabonate, Mazif Don, Medridone, Meprednisone, Methylprednisolone, Mometasone furoate, Paramethasone, Predniscarbate, Prednisolone, Prednisolone 25-diethylaminoacetate, Prednisolone sodium phosphate, Prednisone, Prednisbal, Prednilidene, Limec Solon, thixocortol, triamcinolone, triamcinolone acetonide, triamcinolone bentonide, triamcinolone hexaacetonide, and salts and / or derivatives thereof. In certain claims, the compounds of the present invention may also be used in combination with additional pharmaceutical active agents to treat nausea. Examples of agents that can be used to treat nausea include: dronabinol; Granistron; Metoclopramide; Ondansetron; And prochlorperazine; Or a pharmaceutically acceptable salt thereof.

Since one aspect of the present invention contemplates treating a disease / condition with a combination of pharmaceutically active compounds that can be administered separately, the present invention further relates to combining separate pharmaceutical compositions in kit form. . The kit comprises two separate pharmaceutical compositions, a compound of the invention, and a second pharmaceutical compound. The kit comprises a container containing a separate composition, for example a separate bottle or a separate foil packet. Further examples of containers include syringes, boxes, and bags. In some claims, the kit includes instructions for the use of separate components. The kit form is particularly effective when the separate components are preferably administered in different dosage forms (eg oral and parenteral), at different dosage intervals, or when titration of the individual components of the combination by a specialist is desired. It is advantageous.

The compounds of the present invention can be administered as pharmaceutically acceptable salts, esters, amides or prodrugs. The term "salt" refers to the inorganic and organic salts of the compounds of the present invention. Salts can be prepared in situ during the final isolation and purification of the compound, or by reacting the purified compound in free base or free acid form separately with a suitable organic or inorganic base or acid, and isolating the salt so formed. . Representative salts include hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, Fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate and laurylsulfonate salts and the like. Salts include ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, 247riethylamine, ethylamine, as well as cations based on alkali and alkaline earth metals such as sodium, lithium, potassium, calcium, magnesium, etc. Non-toxic ammonium cations, quaternary ammonium cations, and amine cations, including but not limited to and the like. For example, S. M. Berge, et al., "Pharmaceutical Salts," J Pharm Sci, 66: 1-19 (1977).

The term "prodrug" refers to a compound that is converted in vivo to produce the compound of the present invention. The transformation can occur by various mechanisms, such as through hydrolysis in blood. A discussion of the use of prodrugs is described in T. Higuchi and W. Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the A.C.S. Provided by the Symposium Series, Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.

Gritty example, when the compounds of the invention containing a carboxylic acid functional group prodrugs, a hydrogen atom of the acid group (C ₁ -C ₈₎ alkyl, (C ₂ -C ₁₂₎ alkanoyloxy-methyl, 4 to 9 carbon 1- (alkanoyloxy) ethyl with atoms, 1-methyl-1- (alkanoyloxy) ethyl with 5 to 10 carbon atoms, alkoxycarbonyloxymethyl with 3 to 6 carbon atoms, 4 1- (alkoxycarbonyloxy) ethyl with 7 to 7 carbon atoms, 1-methyl-1- (alkoxycarbonyl) ethyl with 5 to 8 carbon atoms, N with 3 to 9 carbon atoms -(Alkoxycarbonyl) aminomethyl, 1-N- (alkoxycarbonyl) aminomethyl having 4 to 10 carbon atoms, 3-phthalidyl, 4-crotonolactonyl, gamma-butyrolactone-4 -Yl, di-N, N- (C ₁ -C ₂ ) alkylamino (C ₂ -C ₃ ) alkyl (eg β-dimethylaminoethyl), carbamoyl- (C ₁ -C ₂ ) alkyl, N , N-di (C ₁ -C ₂ ) alkylcarbamoyl- (C ₁ -C ₂₎ alkyl and piperidino- may include a ₃₎ is substituted with an alkyl, such as formed ester, pyrrolidino-or morpholino (C _2.

Similarly, when a compound of the present invention comprises an alcohol functional group, the prodrug may be prepared by the hydrogen valence of the alcohol group (C ₁ -C ₆ ) alkanoyloxymethyl, 1-((C ₁ -C ₆ ) alkanoyloxy) ethyl , 1-methyl-1-((C ₁ -C ₆ ) alkanoyloxy) ethyl, (C ₁ -C ₆ ) alkoxycarbonyloxymethyl, N- (C ₁ -C ₆ ) alkoxycarbonylaminomethyl, succinct Noyl, (C ₁ -C ₆ ) alkanoyl, α-amino (C ₁ -C ₄ ) alkanoyl, arylacyl and α-aminoacyl, or α-aminoacyl-α-aminoacyl Wherein each α-aminoacyl group is independently a naturally occurring L-amino acid, -P (O) (OH) ₂ , -P (O) (O (C ₁ -C ₆ ) alkyl) ₂ or glycosyl ( Radicals resulting from the removal of hydroxyl groups in the hemiacetal form of carbohydrates).

The compounds of the present invention may contain asymmetric centers or chiral centers and therefore exist in different stereoisomeric forms. It is contemplated that all stereoisomeric forms of the compounds as well as mixtures thereof, including racemic mixtures, form part of the present invention. In addition, the present invention contemplates all geometric and positional isomers. For example, when the compound contains a double bond, both cis and trans forms (denoted as Z and E, respectively) as well as mixtures are contemplated.

Mixtures of stereoisomers, such as diastereomeric mixtures, can be separated into their individual stereochemical components by known methods such as chromatography and / or fractional crystallization based on their physical chemical differences. Enantiomers also convert enantiomeric mixtures into appropriate diastereomeric mixtures by reacting with appropriate optically active compounds (eg alcohols), separating diastereomers, and converting individual diastereomers to the corresponding pure enantiomers. (E.g., hydrolysis).

The compounds of the present invention may exist in unsolvated forms as well as solvated forms as pharmaceutically acceptable solvents such as water (hydrates), ethanol and the like. The present invention contemplates and includes both solvated and unsolvated forms.

It is also possible for compounds of the invention to exist in different tautomeric forms. All tautomers of the compounds of the invention are contemplated. Those skilled in the art will appreciate that the compound names and structures included herein may be based on specific tautomers of the compounds. The name or structure for only one particular tautomer may be used, but unless stated otherwise all tautomers are intended to be encompassed by the present invention.

In addition, the present invention includes compounds synthesized in vitro using laboratory techniques such as those well known to synthetic chemists; Or compounds that can be synthesized using in vivo techniques, such as through metabolism, fermentation, digestion, and the like. It is also contemplated that the compounds of the present invention may be synthesized using a combination of in vitro and in vivo techniques.

The compounds of the present invention can exist in a variety of solid and amorphous states, including crystalline states. Different crystalline states (also called polymorphs) and amorphous states of the compounds are contemplated as part of the present invention.

Example

The examples set forth below illustrate the specific claims of the present invention. These examples are considered representative and are not intended to limit the scope of the claims in any way.

The following abbreviations may be used herein:

To about

Ac acetate

Ac ₂ O Acetic anhydride

AcOH acetic acid

Al ₂ O ₃ Aluminum Oxide

br wide

Boc tert-butyloxycarbonyl

B (OiPr)₃ Triisopropyl borate

B (Oallyl)₃ Triallyl borate

B (OCH₂CF₃)₃ Tris (2,2,2-trifluoroethyl) borate

B (On-Bu)₃ tree-n-Butyl borate

Calcd Calculated

CO ₂ CO2

CSA 10-camphorsulfonic acid

d day or doublet

DBU 1,8-diazabicyclo [5.4.0] undes-7-yen

DCE dichloroethane

DCM dichloromethane

DEA diethylamine

Dess-Martin periodinane 1,1,1-triacetoxy-1,1-dihydro-1,2-

Benziodoxol-3- (1H) -one

DIPEA or DIEA diisopropylethylamine

DMA N, N-dimethylacetamide

DMF N, N-dimethylformamide

DMSO dimethyl sulfoxide

EDC N-ethyl-N '-(3-

Dimethylaminopropyl) carbodiimide

ee or e.e. Enantiomeric excess

ELISA enzyme-linked immunosorbent assay

eq or equiv equivalent

ESI or ES Electrospray Ionization

Et ethyl

Et ₂ O diethyl ether

EtOAc ethyl acetate

Et ₃ N triethylamine

EtOH ethyl alcohol

EtI Ethyl Iodide

g gram

GC Gas Chromatography

h hours

H ₂ hydrogen gas

HCl hydrochloric acid

¹ H NMR proton nuclear magnetic resonance spectroscopy

HATU 1- [bis (dimethylamino) methylene] -1H-1,2,3-triazole

Rho [4,5-b] pyridinium 3-oxide hexafluorophosphate

H ₂ O water

HPLC high performance liquid chromatography

H ₂ SO ₄ sulfuric acid

Hz hertz

IP intraperitoneal

IPA Isopropyl Alcohol

K ₂ CO ₃ Potassium Carbonate

KF Karl Fisher Titration

KHMDS hexamethyldisilazide potassium

KOAc Potassium Acetate

KOH Potassium Hydroxide

K ₃ PO ₄ Potassium Phosphate

KOtBu Potassium tert-butoxide

L liter

LAH Lithium Aluminum Hydride

LCMS, LC-MS, or LC / MS Liquid Chromatography Mass Spectrometry

LHMDS lithium hexamethyldisilazide

m multiplet

mm millimeter

M mol (mol / L) or mass

Me methyl

MeCN acetonitrile

MeI Iodinemethane

MeOH Methyl Alcohol

MeTHF 2-methyltetrahydrofuran

Me ₃ SI trimethylsulfonium iodide

MeNH₂ Methylamine

Me ₂ NH Dimethylamine

mg milligram

MgSO ₄ Magnesium Sulfate

MHz MHz

μm micrometer

μL microliters

min min

mL milliliters

mm millimeter

mol mol

MS mass spectrometry

MSA methanesulfonic acid

MsCl methanesulfonyl chloride

MTBE methyl tert-butyl ether

m / z mass-to-charge ratio

N normal concentration (Eq / L)

N ₂ nitrogen gas

nBuLi n-butyllithium

NaCl Sodium Chloride

Na ₂ CO ₃ Sodium Carbonate

NaHCO ₃ Sodium Bicarbonate

NaH ₂ PO ₄ Sodium Dihydrogen Phosphate

NaNO ₂ Sodium Nitrite

NaOH sodium hydroxide

NaOtBu Sodium Tert-Butoxide

Na ₂ SO ₄ Sodium Sulfate

Na ₂ S ₂ O ₃ Sodium Thiosulfate

NH ₃ ammonia, azan

NH ₄ Cl Ammonium Chloride

NH ₄ OH Ammonium Hydroxide

NMP 1-methyl-2-pyrrolidinone

NMR nuclear magnetic resonance spectroscopy

OMe methoxy

PO oral

+ ve quantity

Ph phenyl

PhMe Toluene

PMB p -methoxybenzyl

POCl ₃ phosphoryl chloride

ppm parts per million

prep aliquot

psi pounds per square inch

q quartet

QD once daily

QNMR Quantitative NMR

Rac racemic

RBF round bottom flask

RT, rt, or r.t. Room temperature

s singlet

sat. Or satd or sat'd saturated

SFC Supercritical Fluid Chromatography

SIMes 1,3-bis (2,4,6-trimethylphenyl) -4,5-dihydroimidazole

2-ylidene

SiO ₂ silica

SOCl ₂ thionyl chloride

t triplet

TBDPS tert-butyldiphenylsilyl

TBS tert-butyldimethylsilyl

TEMPO (2,2,6,6-tetramethylpiperidin-1-yl) oxydanyl

t-BuOH tert-butanol

TFA Trifluoroacetic Acid

THF tetrahydrofuran

Ti (O i Pr) ₄ titanium isopropoxide

TLC thin layer chromatography

TsOH Toluene Sulfonic Acid

UV ultraviolet

volume per v / v volume

wt% wt%

Note that when percentage (%) is used in connection with the liquid, it is a volume percentage for the solution. When used with a solid, this is the percentage relative to the solid composition.

General Synthetic Scheme

Unless stated otherwise, starting materials and reagents used in the preparation of these compounds may be purchased from commercial suppliers such as Aldrich Chemical Co., Milwaukee, WI, or references (eg, Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), Advanced Organic Chemistry of March, (John Wiley and Sons, 4th Edition) and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989) according to the procedures known to those skilled in the art. .

Starting materials for the following synthetic methods can be found in General Methods and General Synthesis for Intermediates. The synthesis of some of the starting materials and intermediates is disclosed in US Pat. No. 9,562,061 and PCT / US17 / 19336, respectively, which are incorporated herein by reference in their entirety for all purposes. These synthetic methods are merely illustrative of some of the ways in which the compounds of the present invention may be synthesized, and various modifications may be made to these methods and will be suggested to those skilled in the art with reference to the present disclosure. The starting materials and intermediates, and the final product of the reaction can be isolated and purified using conventional techniques, including but not limited to filtration, distillation, crystallization, chromatography, and the like, as needed. Such materials can be characterized using conventional means, including physical constants and spectral data.

Unless stated to the contrary, the reactions described herein occur at atmospheric pressure over a temperature range of about -78 ° C to about 150 ° C, more preferably about 0 ° C to about 125 ° C, and most preferably about room temperature (or Room temperature), for example at 22 ° C.

IUPAC names were generated using either ACD / Name v2015 or ChemBioDraw Ultra 12.

General Method 1: Enone Synthesis

General Method 2: Enon Synthesis

General Method 3: Converting Enones to Aldehyde through Epoxide

General Method 4: Converting Enones to Aldehyde via Epoxide

General method 5: convert ketone to aldehyde through dithiane

General method 6: convert ketone to aminoalcohol via epoxide

General Method 7: Converting Enones to Amino Ethers

General Method 8: Reductive Amination with NaBH (OAc) ₃

General Method 9: Reductive Amination with NaBH _4, Ti (O i Pr) ₄ , and an Amine Salt

General Method 10: Reductive Amination with NaBH (OAc) ₃ and an Amine Salt

General Method 11: Reductive Amination with NaBH (OAc) ₃ , Ti (OiPr) ₄ , and an Amine Salt

General Method 12: Reductive Amination with NaBH (OAc) ₃ and AcOH

General Method 13: Reductive Amination with NaBH ₃ CN and AcOH

Example 1

(1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-Chloro-7'-ethoxy-7 '-((9aS) -hexahydropyrazino [2 , 1-c] [1,4] oxazine-8 (1H) -ylmethyl) -11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1, 22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraene ] -15'-one 13 ', 13'-dioxide

General Method 3 (Steps 1 to 3), General Method 7 (Step 1), General Method 8 (Step 4)

Step 1: (1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-11 ', 12'-dimethyl-3,4-dihydro-2H , 15'H-dicespiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6-0.0-19,24-] penta Cosa [8,16,18,24] tetraen-7 ', 2' '-oxirane] -15'-one 13', 13'-dioxide

A 250 mL three-necked flask equipped with a thermocouple, nitrogen inlet and septum (1S, 3'R, 6'R, 8'E, 11'S, 12'R) -6-chloro-11 ', 12'- Dimethyl-3,4-dihydro-2H, 7'H, 15'H-spiro [naphthalene-1,22 '[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0 ~ 3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraene] -7 ', 15'-dione 13', 13'-dioxide (10.05 g, 15.48 mmol) and Filled with trimethylsulfonium iodide (4.79 g, 23.47 mmol). Dimethyl sulfoxide (80 mL) and tetrahydrofuran (20 mL) were added and the reaction was cooled to 5 ° C. using an ice bath. The reaction was treated with 1 M potassium t-butoxide in THF (39.0 mL, 39.0 mmol) through a syringe over 20 minutes. The reaction was quenched with glacial acetic acid (2.20 mL, 38.1 mmol) and stirred for 1 minute. The mixture was poured into isopropyl acetate (200 mL) and washed with water (200 mL). The aqueous layer was extracted with isopropyl acetate (100 mL) and the combined organic layers were washed with water (3 x 200 mL) and brine (60 mL) and dried over Na ₂ S0 ₄ . The solution was filtered and the filtrate was concentrated under reduced pressure. The residue was azeotrope with DCM (2 × 200 mL) and then dissolved in DCM (40 mL). Heptane (400 mL) was added dropwise over 1 hour, then the mixture was stirred for 30 minutes. The solid was filtered and dried for 3 hours using nitrogen purge on frit to give 8.60 g of (1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-11 ' , 12'-dimethyl-3,4-dihydro-2H, 15'H-diisspiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7. 2.0 ~ 3,6 ~ .0 ~ 19,24 ~] Pentacosa [8,16,18,24] tetraen-7 ', 2''-oxirane]-15'-one13',13'-dioxide Was obtained as a white solid. ¹ H NMR (400 MHz, Dichloromethane-d2) δ ppm 8.08 (s, 1 H), 7.72 (d, J = 8.41 Hz, 1 H), 7.22 (d, J = 0.98 Hz, 1 H), 7.19 (dd, J = 8.41, 2.35 Hz, 1H), 7.09 (d, J = 2.15 Hz, 1H), 6.83-6.95 (m, 2H), 5.73-5.91 (m, 1H), 5.60 (d , J = 15.26 Hz, 1H), 4.20 (q, J = 7.24 Hz, 1H), 4.01-4.14 (m, 2H), 3.92 (dd, J = 15.45, 4.50 Hz, 1H), 3.73 ( br d, J = 14.28 Hz, 1 H), 3.20 (d, J = 14.28 Hz, 1 H), 2.96 (dd, J = 15.55, 6.55 Hz, 1 H), 2.65-2.85 (m, 2H), 2.47 (d, J = 5.48 Hz, 1 H), 2.25-2.43 (m, 2 H), 1.73-2.08 (m, 9 H), 1.60-1.72 (m, 1 H), 1.33-1.44 (m, 4 H), 1.03 (br d, J = 5.87 Hz, 3 H).

Step 2: (1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-ethoxy-7 '-(hydroxymethyl) -11' , 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0 ~ 3,6 ~ .0 ~ 19,24 ~] Pentacosa [8,16,18,24] tetraene] -15'-on 13 ', 13'-dioxide

1 L three-necked flask equipped with thermocouple, nitrogen adapter and diaphragm (1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-11 ', 12' -Dimethyl-3,4-dihydro-2H, 15'H-dispiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diaza tetracyclo [14.7.2.0-3] , 6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraen-7 ', 2''-oxirane]-15'-one13',13'-dioxide (10.22 g , 16.72 mmol) and 2-methyltetrahydrofuran (300 mL). Triethyl borate (50 mL, 291 mmol) was added via syringe and the reaction placed on a heating block preheated to 65 ° C. After 12 hours, the reaction was cooled to room temperature overnight. The reaction mixture was quenched with saturated NaHCO _{3 (} 100 mL) and stirred for 10 minutes. The aqueous layer was extracted with EtOAc (3 x 50 mL) and the combined organic layers were washed with brine (50 mL), dried over Na ₂ S0 ₄ and filtered. The filtrate was evaporated onto silica gel and purified by flash chromatography (Isco (330 g)) eluting with 0.3% AcOH in EtOAc to 0.3% AcOH in heptane (0: 1 → 1: 1) to give 6.27 g of (1S). , 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-ethoxy-7 '-(hydroxymethyl) -11', 12'-di Methyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diaza tetracyclo [14.7.2.0-3,6] .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraen] -15'-one 13 ', 13'-dioxide was obtained. MS (ESI, cation) m / z 657.3 (M + l) ⁺ .

Step 3: (1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-ethoxy-11 ', 12'-dimethyl-15' Oxo-3,4-dihydro-2H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diaza tetracyclo [14.7.2.0-3,6-0.0 ... 19,24 ~] pentacosa [8,16,18,24] tetraene] -7'-carbaldehyde 13 ', 13'-dioxide

A 250 mL three-necked flask equipped with a thermocouple, nitrogen adapter and diaphragm was used as the starting material (1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7 ' -Ethoxy-7 '-(hydroxymethyl) -11', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13 ] Thia [1,14] diaza tetracyclo [14.7.2.0-3,6-0.0-19,24-] pentacosa [8,16,18,24] tetraene] -15'-one 13 ', Charged with 13'-dioxide (6.27 g, 7.54 mmol), DCM (50 mL) and dimethyl sulfoxide (20 mL). The solution was cooled in an ice bath (0 ° C.) and N, N-diisopropylethylamine (6.6 mL, 37.8 mmol) was added followed by sulfur trioxide pyridine complex (3.02 g, 18.97 mmol) once over 15 minutes. The ice bath was removed and warmed to room temperature for 2 hours. The reaction mixture was poured into isopropyl acetate (200 mL) and the solution was washed with water (200 mL). The aqueous layer was extracted with EtOAc (1 x 100 mL) and the combined organic layers were washed with 50% saturated NH ₄ Cl (2 x 100 mL), water (50 mL), brine (50 mL) and dried over Na ₂ S0 ₄ . I was. The solution was filtered and the filtrate was concentrated under reduced pressure to give a pale yellow solid. The solid was dissolved in EtOAc and evaporated onto silica gel, purified by flash chromatography (Isco (220 grams)) eluting with 0.3% AcOH in EtOAc (0.3% AcOH in heptane (0: 1 → 1: 1)) to 4.44. g of (1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-ethoxy-11 ', 12'-dimethyl-15'- Oxo-3,4-dihydro-2H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazettracyclo [14.7.2.0-3,6-0.0-19 , 24-] pentacosa [8,16,18,24] tetraene] -7'-carbaldehyde 13 ', 13'-dioxide was obtained as a white solid. MS (ESI, cation) m / z 655.3 (M + l) ⁺ .

Step 4: (1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-ethoxy-7 '-((9aS) -hexahydropyra Zino [2,1-c] [1,4] oxazine-8 (1H) -ylmethyl) -11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene -1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6-0.0-19,24-] pentacosa [8,16,18,24 ] Tetraene] -15'-on 13 ', 13'-dioxide

Preparation of the amine free base: (S) -octahydropiperazino [2,1-c] morpholine dihydrochloride (7.04 g, 32.7 mmol; Synthonix, NC) in DCM (100 mL) To a room temperature suspension of Wake Forest, sodium methoxide (25 wt% solution in methanol, 15 mL, 65.6 mmol) was added and the reaction stirred for 2 h. The solvent was removed under reduced pressure and the residue was stirred for 1 h in EtOAc (100 mL). The solution was filtered and the filtrate was concentrated under reduced pressure to give (S) -octahydropyrazino [2,1-c] [1,4] oxazine (4.33 g) as a pale yellow oil. ¹ H NMR (400 MHz, Dichloromethane-d2) δ ppm 3.70-3.82 (m, 1 H), 3.61-3.67 (m, 1 H), 3.52-3.60 (m, 1 H), 3.15 (t, J = 10.47 Hz, 1 H), 2.79-2.93 (m, 2 H), 2.60-2.71 (m, 2 H), 2.55 (br d, J = 11.54 Hz, 1 H), 2.27-2.39 (m, 2 H ), 2.05-2.21 (m, 2H).

(1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-ethoxy-11 'in 1,2-dichloroethane (40 mL) , 12'-dimethyl-15'-oxo-3,4-dihydro-2H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatracyclo [14.7. 2.0 to 3,6 to .0 to 19,24 to] pentacosa [8,16,18,24] tetraene] -7'-carbaldehyde 13 ', 13'-dioxide (4.44 g, 6.51 mmol) To the solution was added a solution of (S) -octahydropyrazino [2,1-c] [1,4] oxazine (2.91 g, 18.01 mmol) in 1,2-dichloroethane (5 mL) and the reaction Was stirred for 2 hours. To the reaction was added sodium triacetoxyborohydride (0.350 g, 1.651 mmol) as a solid. Further sodium triacetoxyborohydride (0.350 g, 1.651 mmol) was added until the reaction was complete. The reaction was quenched with saturated NH 4 Cl (40 mL) and the layers separated. The aqueous layer was extracted with DCM (2 ×) and the combined organic layers were washed with 1 M KH 2 PO 4 (40 mL). The organic layer was dried over Na 2 SO 4, filtered, and the filtrate was concentrated under reduced pressure and stored in a freezer. The residual material was dissolved in DCM and evaporated onto silica gel, EtOAc: heptane: MeOH: DCM (0: 1: 0: 0 → 3: 2: 0: 0 → 0: 0: 1: 49 → 0: 0: Purification by flash chromatography (Isco (330 grams)) eluting with 3: 47) gave 3.63 g of an off-white solid. The material was stirred over MeOH (15 mL) for 1 h. MeOH (30 mL) was added to the thick slurry to maintain good stirring. After an additional hour, the solvent was removed under reduced pressure and the residue was dried in vacuo. The solid was dried for 24 hours under nitrogen purge / vacuum to give 3.10 g of (1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-ethoxy -7 '-((9aS) -hexahydropyrazino [2,1-c] [1,4] oxazin-8 (1H) -ylmethyl) -11', 12'-dimethyl-3,4- Dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazettracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 Pentacosa [8,16,18,24] tetraen] -15'-one 13 ', 13'-dioxide was obtained as a white solid. MS (ESI, cation) m / z 781.3 (M + l) ⁺ . ¹ H NMR (400 MHz, Dichloromethane-d2) δ ppm 7.72 (d, J = 8.41 Hz, 1 H), 7.23 (s, 1 H), 7.17 (dd, J = 8.41, 1.96 Hz, 1 H) , 7.09 (d, J = 1.96 Hz, 1 H), 6.89 (s, 2 H), 5.58-5.75 (m, 1 H), 5.43 (br d, J = 15.85 Hz, 1 H), 4.15 (q, J = 6.85 Hz, 1 H), 4.07 (s, 2 H), 4.01 (br d, J = 15.45 Hz, 1 H), 3.74-3.82 (m, 1 H), 3.71 (br d, J = 14.08 Hz , 1 H), 3.54-3.66 (m, 3 H), 3.43-3.52 (m, 1 H), 3.27 (d, J = 14.28 Hz, 1 H), 3.17 (br t, J = 10.37 Hz, 1 H ), 2.89-3.03 (m, 2H), 2.72-2.85 (m, 2H), 2.58-2.71 (m, 2H), 2.54 (m, 2H), 2.48 (br d, J = 14.28 Hz, 1 H), 2.20-2.40 (m, 5 H), 2.03-2.20 (m, 4 H), 1.65-2.00 (m, 6 H), 1.54-1.64 (m, 2 H), 1.41 (d, J = 7.24 Hz, 3H), 1.30-1.38 (m, 4H), 1.01 (br d, J = 5.67 Hz, 3H).

Example 2

(1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-ethoxy-11 ', 12'-dimethyl-7'-(( 4- (3-oxetanyl) -1-piperazinyl) methyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [ 1,14] diatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraene] -15'-one 13 ', 13'- Dioxide

(1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-ethoxy-11 'in 1,2-dichloroethane (1 mL) , 12'-dimethyl-15'-oxo-3,4-dihydro-2H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatracyclo [14.7. 2.0 to 3,6 to .0 to 19,24 to] Pentacosa [8,16,18,24] tetraene] -7'-carbaldehyde 13 ', 13'-dioxide (0.050 g, 0.076 mmol) To the solution was added 1- (oxetan-3-yl) piperazine (0.100 mL, 0.823 mmol, Astatech Inc., Bristol, PA) with a syringe and the reaction was stirred for 1 hour. To the reaction was added sodium triacetoxyborohydride (0.050 g, 0.236 mmol) as a solid and the reaction was stirred overnight. The reaction was quenched with pH 7 buffer and the layers separated. The aqueous layer was extracted with DCM (3 ×) and the combined organic layers were concentrated under reduced pressure. The residue was dissolved in MeOH and eluted with 0.1% TFA-H ₂ O: 0.1% TFA CH ₃ CN (7: 3-> 5:95) reverse phase HPLC (Gilson; Gemini-NX 10m C18 110 x AXIA, 100 x) 50 mm column). The desired product containing fractions were combined and the buffer solution of pH 7; by treatment with _{(1 M KH 2 PO 4/} 1 MK 2 HPO 4 5 mL) the layers were separated. The aqueous layer was extracted with EtOAc (3 ×) and the combined organic layers were washed with brine and dried over Na ₂ SO ₄ . The solution was filtered and concentrated under reduced pressure (1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-ethoxy-11 ', 12'- Dimethyl-7 '-((4- (3-oxetanyl) -1-piperazinyl) methyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-[ 20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraen] -15 ' -On 13 ', 13'-dioxide (47 mg, 79%) was obtained as a white crystalline solid. MS (ESI, cation) m / z 781.2 (M + l) ⁺ . ¹ H NMR (400 MHz, Dichloromethane-d2) δ ppm 8.07 (br s, 1 H), 7.71 (d, J = 8.41 Hz, 1 H), 7.23 (s, 1 H), 7.17 (dd, J = 8.51, 2.25 Hz, 1 H), 7.08 (d, J = 2.15 Hz, 1 H), 6.82-6.93 (m, 2 H), 5.61-5.78 (m, 1 H), 5.45 (br d, J = 15.85 Hz, 1 H), 4.56-4.66 (m, 2 H), 4.44-4.54 (m, 2 H), 4.15 (br d, J = 7.04 Hz, 1 H), 4.03-4.10 (m, 2 H) , 3.99 (br d, J = 14.67 Hz, 1 H), 3.70 (br d, J = 14.28 Hz, 1 H), 3.61 (quin, J = 7.24 Hz, 1 H), 3.35-3.52 (m, 2 H ), 3.26 (d, J = 14.28 Hz, 1 H), 2.95 (br dd, J = 14.87, 9.98 Hz, 1 H), 2.72-2.85 (m, 2H), 2.59-2.71 (m, 2H) , 2.46-2.57 (m, 4 H), 2.24-2.41 (m, 4 H), 2.02-2.19 (m, 4 H), 1.78-1.98 (m, 3 H), 1.70 (br s, 1 H), 1.57 (br d, J = 6.26 Hz, 4H), 1.29-1.45 (m, 7H), 1.00 (br d, J = 5.09 Hz, 3H).

Example 3

(1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-methoxy-11 ', 12'-dimethyl-7'-(( 4- (3-oxetanyl) -1-piperazinyl) methyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [ 1,14] diatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraene] -15'-one 13 ', 13'- Dioxide

General Method 5 (Steps 1-3)

Step 1: (1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7 '-(1,3-dithiane-2-yl) -7 '-Hydroxy-11', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] dia Jatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ', 13'-dioxide and (1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7 '-(1,3-dithiane-2-yl) -7'-hydroxy-11', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0 ~ 3,6 ~ .0 ~ 19,24 ~] Pentacosa [8,16,18,24] tetraene] -15'-on 13 ', 13'-dioxide

To a 250 mL round bottom flask was added 1,3-dithiane (4.79 g, 39.8 mmol) and THF (100 mL). The mixture was cooled to −78 ° C. and n-butyllithium (1.6 M solution in hexanes, 22.5 mL, 36.1 mmol) was added over 8 minutes. The solution was stirred for 30 min in a bath at -78 ° C. In a separate 100 mL flask (1S, 3'R, 6'R, 8'E, 11'S, 12'R) -6-chloro-11 ', 12'-dimethyl-3,4-dihydro-2H, 7'H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~ ] Pentacosa [8,16,18,24] tetraene] -7 ', 15'-dione 13', 13'-dioxide and THF (5 mL) were added. To this was added a lanthanum (III) chloride bis (lithium chloride) complex solution (0.6 M in THF, 60.1 mL, 36.1 mmol) and stirred at room temperature for 5 minutes. The solution was then cooled to −78 ° C. and added to Ditian solution via cannula. After 2.5 hours at −78 ° C., the solution was treated with saturated NH ₄ Cl and water. The pH of the solution was adjusted to pH = 4 with aqueous 10% citric acid and aqueous NaHCO ₃ . The solution was extracted with EtOAc and the combined extracts were filtered through celite. The filtrate was washed with water and brine, dried (Na ₂ SO ₄ ) and concentrated to (1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7 '-(1,3-dithiane-2-yl) -7'-hydroxy-11', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraene -15'-one 13 ', 13'-dioxide and (1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-(1,3-di Thian-2-yl) -7'-hydroxy-11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-[20] oxa [13 ] Thia [1,14] diaza tetracyclo [14.7.2.0-3,6-0.0-19,24-] pentacosa [8,16,18,24] tetraene] -15'-one 13 ', A mixture of 13'-dioxide could be obtained as a brown oil, which was used for the next step. MS (ESI, cation) m / z 717.5 (M + H) ⁺ .

Step 2: (1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7 '-(1,3-dithiane-2-yl) -7 '-Methoxy-11', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] dia Jatetracyclo [14.7.2.0-3,6-0.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ', 13'-dioxide and (1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7 '-(1,3-dithiane-2-yl) -7'-methoxy-11', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0 ~ 3,6 ~ .0 ~ 19,24 ~] Pentacosa [8,16,18,24] tetraene] -15'-on 13 ', 13'-dioxide

(1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7 '-(1,3-dithiane-2-yl)-in a separate vial 7'-hydroxy-11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-[20] oxa [13] thia [1,14] Diazatetracyclo [14.7.2.0-3,6-0.0-19,24-] Pentacosa [8,16,18,24] tetraene] -15'-one 13 ', 13'-dioxide and (1S , 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7 '-(1,3-ditian-2-yl) -7'-hydroxy-11' , 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0 ~ 3,6 ~ .0 ~ 19,24 ~] Pentacosa [8,16,18,24] tetraene] -15'-one 13 ', 13'-dioxide (6.81 g, 9.49 mmol) and THF (100 mL) was added. The mixture was cooled to 0 ° C. and potassium bis (trimethylsilyl) amide (1 M in THF, 38.0 mL, 38.0 mmol) was added over 10 minutes. The solution was stirred at 0 ° C. for 5 minutes before iodine methane (2.36 mL, 38.0 mmol) was added over 3 minutes. After 2.5 hours at 0 ° C., the solution was poured into saturated NH ₄ Cl and the pH was adjusted to 4 using 1 M citric acid. The solution was extracted with EtOAc and the combined extracts were washed with brine, dried (Na ₂ SO ₄ ) and concentrated on silica. Purification by silica gel chromatography (0% to 35% EtOAc / heptanes, both comprising 0.3% AcOH v / v, 330 g Redi-Sep Gold column) gave: (1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7 '-(1,3-dithia-2--2-)-7'-methoxy-11', 12 ' -Dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3, 6 ~ .0 ~ 19,24 ~] Pentacosa [8,16,18,24] tetraen] -15'-one 13 ', 13'-dioxide (1.66 g, 2.27 mmol, 24% yield) MS (ESI , Cation) m / z 731.5 (M + H) ⁺ and (1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7 '-(1,3- Dithiane-2-yl) -7'-methoxy-11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-[20] oxa [ 13] thia [1,14] diatetracyclo [14.7.2.0-3,6-0.0-19,24-] pentacosa [8,16,18,24] tetraene] -15'-one 13 ' , 13'-dioxide (4.69 g, 6.41 mmol, 68% yield) MS (ESI, cation) m / z 731.5 (M + H) ⁺ .

Step 3: (1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-methoxy-11 ', 12'-dimethyl-15' Oxo-3,4-dihydro-2H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diaza tetracyclo [14.7.2.0-3,6-0.0 ... 19,24 ~] pentacosa [8,16,18,24] tetraene] -7'-carbaldehyde 13 ', 13'-dioxide

In a 250 mL round bottom flask equipped with a reflux condenser (1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7 '-(1,3- Dithiane-2-yl) -7'-methoxy-11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-[20] oxa [ 13] thia [1,14] diatetracyclo [14.7.2.0-3,6-0.0-19,24-] pentacosa [8,16,18,24] tetraene] -15'-one 13 ' , 13'-dioxide (1.63 g, 2.23 mmol), acetonitrile (40 mL) and water (10 mL) were added. The mixture was heated to 50 ° C. and calcium carbonate (1.12 g, 11.1 mmol) and iodine methane (1.38 mL, 22.3 mmol) were added. After 23 hours at 50 ° C., the solution was poured into saturated NH ₄ Cl and water and extracted with EtOAc. The combined extracts were washed with brine and then dried (Na ₂ SO ₄ ) and concentrated on silica. Purification by silica gel chromatography (0% to 40% EtOAc / heptanes (both containing 0.3% AcOH), Silicycle HP 120 g column) (1S, 3'R, 6'R, 7'R, 8 'E, 11'S, 12'R) -6-chloro-7'-methoxy-11', 12'-dimethyl-15'-oxo-3,4-dihydro-2H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraene -7'-carbaldehyde 13 ', 13'-dioxide was obtained as a white solid (1.34 g, 2.09 mmol, 94% yield). MS (ESI, cation) m / z 641.3 (M + H) ⁺ .

Step 4: (1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-methoxy-11 ', 12'-dimethyl-7' -((4- (3-oxetanyl) -1-piperazinyl) methyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13 ] Thia [1,14] diaza tetracyclo [14.7.2.0-3,6-0.0-19,24-] pentacosa [8,16,18,24] tetraene] -15'-one 13 ', 13'-dioxide

(1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-methoxy-11 ', 12'-dimethyl-15' Oxo-3,4-dihydro-2H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diaza tetracyclo [14.7.2.0-3,6-0.0 ... 19,24 ~] pentacosa [8,16,18,24] tetraene] -7'-carbaldehyde 13 ', 13'-dioxide (0.135 g, 0.211 mmol), 1,2-dichloroethane (2.0 mL ) And 1- (oxetan-3-yl) piperazine (0.090 g, 0.632 mmol, AstaTech, Inc.) were added. The solution was stirred at rt for 1 h. To this solution was added sodium triacetoxyborohydride (0.011 g, 0.053 mmol). After stirring overnight at room temperature, additional sodium triacetoxyborohydride (0.011 g, 0.053 mmol) was added until the reaction was complete. The reaction was carefully quenched with MeOH, stirred for 1 h and then filtered for Prep-HPLC purification. Prep-HPLC (column: Phenomenex Luna 5 μ C18, 100 μs, 150 x 20 mm; solvent: A = water (0.1% TFA), B = (R) (0.1% TFA), 30 mL / min, at 18 minutes The solution was purified by 30% B to 100% B over then 2 minutes at 100% B) and the fractions containing product were treated with aqueous pH 7 buffer (KH ₂ PO ₄ / K ₂ HPO ₄ series) Extracted with EtOAc. The combined extracts were washed with brine and then dried (Na ₂ SO ₄ ), filtered and concentrated (1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro -7'-methoxy-11 ', 12'-dimethyl-7'-((4- (3-oxetanyl) -1-piperazinyl) methyl) -3,4-dihydro-2H, 15 'H-spiro [naphthalene-1,22'-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6-0.0-19,24-] pentacosa [8 , 16,18,24] tetraen] -15'-one 13 ', 13'-dioxide was obtained as a white solid (0.101 g, 0.132 mmol, 63% yield). ¹ H NMR (400 MHz, Dichloromethane-d2) δ ppm 7.72 (d, J = 9.8 Hz, 1 H), 7.25 (br s, 1 H), 7.16 (br d, J = 8.6 Hz, 1 H) , 7.09 (s, 1 H), 6.89 (s, 2 H), 5.62 (br s, 1 H), 5.37 (br d, J = 14.9 Hz, 1 H), 4.56-4.66 (m, 2 H), 4.52 (br t, J = 5.9 Hz, 2 H), 4.12 (br d, J = 6.5 Hz, 1 H), 4.06 (s, 2 H), 3.98 (br d, J = 14.9 Hz, 1 H), 3.70 (br d, J = 14.1 Hz, 1 H), 3.40-3.52 (m, 1 H), 3.36 (s, 3 H), 3.19-3.30 (m, 1 H), 2.90-3.03 (m, 1 H ), 2.64-2.85 (m, 4 H), 2.45-2.63 (m, 5 H), 2.26-2.41 (m, 4 H), 2.15-2.25 (m, 1 H), 2.02-2.15 (m, 3 H ), 1.78-1.99 (m, 4 H), 1.66-1.76 (m, 1 H), 1.49-1.64 (m, 2 H), 1.40 (br d, J = 7.2 Hz, 4 H), 1.01 (br d , J = 5.7 Hz, 3 H). MS (ESI, cation) m / z 767.3 (M + H) ⁺ .

Example 4

(1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7 '-((9aS) -hexahydropyrazino [2,1-C] [ 1,4] oxazine-8 (1H) -ylmethyl) -7'-methoxy-11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1, 22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraene ] -15'-one 13 ', 13'-dioxide

General method 9

In a 100 mL three neck flask (1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-methoxy-11 ', 12'-die Methyl-15'-oxo-3,4-dihydro-2H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazettracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraene] -7'-carbaldehyde 13 ', 13'-dioxide (0.486 g, 0.758 mmol), DCM (20 mL) and Ethanol (8.0 mL) was added. To this solution was added (9aS) -octahydropiperazino [2,1-c] morpholine dihydrochloride (1.96 g, 9.10 mmol), followed by N, N-diisopropylethylamine (4.0 mL, 22.7 mmol) was added. To the solution was added titanium (iv) isopropoxide (2.24 mL, 7.58 mmol). The solution was stirred at rt for 17 h. To this solution sodium borohydride (0.143 g, 3.79 mmol) was added in three portions. The reaction mixture was stirred at rt. After 18 hours, additional sodium borohydride (35 mg) was added and stirring continued for an additional 24 hours at room temperature. The reaction was carefully quenched with saturated NH ₄ Cl and then diluted with aqueous pH 7 buffer (KH ₂ PO ₄ / K ₂ HPO ₄ series), filtered through celite and extracted with EtOAc. The combined extracts were washed with brine, dried (Na ₂ SO ₄ ), filtered and concentrated to give a white solid. Prep-HPLC (column: Phenomenex Gemini C18, 110 mm 3, 100 x 50 mm; solvent: A = water (0.1% TFA), B = (R) (0.1% TFA), 100 mL / min, 10 over 11 minutes Purify the solid by% B to 100% B, then 2 minutes at 100% B), fraction containing product is treated with aqueous pH 7 buffer (KH ₂ PO ₄ / K ₂ HPO ₄ series) and concentrated Acetonitrile was removed and extracted with EtOAc. The combined extracts were washed with brine, dried (Na ₂ SO ₄ ), filtered and concentrated to (1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro -7 '-((9aS) -hexahydropyrazino [2,1-c] [1,4] oxazin-8 (1H) -ylmethyl) -7'-methoxy-11', 12'-di Methyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diaza tetracyclo [14.7.2.0-3,6] .0-19,24-] Pentacosa [8,16,18,24] tetraen] -15'-one 13 ', 13'-dioxide was obtained as a white solid (0.478 g, 0.622 mmol, 82% yield). ). ¹ H NMR (400 MHz, Dichloromethane-d2) δ ppm 7.72 (d, J = 8.6 Hz, 1 H), 7.26 (s, 1 H), 7.17 (dd, J = 8.5, 2.2 Hz, 1 H) , 7.09 (d, J = 2.3 Hz, 1 H), 6.85-6.93 (m, 2 H), 5.57-5.68 (m, 1 H), 5.35 (s, 1 H), 4.08-4.17 (m, 1 H ), 4.07 (s, 2H), 3.96-4.04 (m, 1H), 3.78 (br d, J = 9.6 Hz, 1H), 3.70 (br d, J = 14.3 Hz, 1H), 3.59 ( br d, J = 10.8 Hz, 2 H), 3.35 (s, 3 H), 3.25 (d, J = 14.3 Hz, 1 H), 3.17 (br s, 1 H), 2.88-3.06 (m, 2 H ), 2.72-2.81 (m, 2 H), 2.58-2.67 (m, 2 H), 2.45-2.54 (m, 3 H), 2.30-2.37 (m, 2 H), 2.17-2.27 (m, 3 H ), 2.07-2.14 (m, 2 H), 2.03-2.07 (m, 1 H), 1.90-1.99 (m, 2 H), 1.81-1.90 (m, 2 H), 1.66-1.75 (m, 1 H ), 1.48-1.65 (m, 4H), 1.36-1.44 (m, 4H), 1.02 (d, J = 6.1 Hz, 3H) MS (ESI, cation) m / z 767.7 (M + H) ⁺ .

Example 5

(1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-methoxy-11 ', 12'-dimethyl-7'-(( 4- (1-methylethyl) -1-piperazinyl) methyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1 , 14] diaza tetracyclo [14.7.2.0-3,6-0.0-19,24-] pentacosa [8,16,18,24] tetraene] -15'-one 13 ', 13'-dioxide

(1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-methoxy-11 ', 12'-dimethyl-15' Oxo-3,4-dihydro-2H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diaza tetracyclo [14.7.2.0-3,6-0.0 ... 19,24 ~] pentacosa [8,16,18,24] tetraene] -7'-carbaldehyde 13 ', 13'-dioxide (0.135 g, 0.211 mmol), 1,2-dichloroethane (2 mL ) And 1-isopropylpiperazine (0.090 g, 0.632 mmol, Across Organics) were added. The solution was stirred at rt for 1 h. To this solution was added sodium triacetoxyborohydride (0.011 g, 0.053 mmol). After 2 hours at room temperature, 0.25 equivalents (four times in total) of sodium triacetoxyborohydride were further added until the reaction was complete. The reaction mixture was carefully quenched with MeOH, stirred for 1 h and then filtered for Prep-HPLC purification. Prep-HPLC (Column: Phenomenex Luna C18, 100 cc, 150 x 21.20 mm; Solvent: A = Water (0.1% TFA), B = (R) (0.1% TFA), 30 mL / min, 30 over 18 minutes Purify the solution by% B to 100% B, then 2 min at 100% B, treat the fractions containing the product with aqueous pH 7 buffer (KH ₂ PO ₄ / K ₂ HPO ₄ series) and with EtOAc Extracted. The combined extracts were washed with brine and then dried (Na ₂ SO ₄ ), filtered and concentrated (1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro -7'-methoxy-11 ', 12'-dimethyl-7'-((4- (1-methylethyl) -1-piperazinyl) methyl) -3,4-dihydro-2H, 15 ' H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6-0.0-19,24-] pentacosa [8, 16,18,24] tetraen] -15'-one 13 ', 13'-dioxide was obtained as a white solid (0.0855 g, 0.113 mmol, 54% yield). ¹ H NMR (400 MHz, Dichloromethane-d2) δ ppm 7.76 (d, J = 8.6 Hz, 1 H), 7.30 (s, 1 H), 7.20 (br d, J = 8.4 Hz, 1 H), 7.13 (s, 1H), 7.00 (d, J = 8.2 Hz, 1H), 6.92 (d, J = 9.0 Hz, 1H), 5.63-5.74 (m, 1H), 5.49 (d, J = 15.8 Hz, 1 H), 4.10 (s, 2 H), 3.96-4.05 (m, 2 H), 3.74 (br d, J = 14.3 Hz, 1 H), 3.46 (s, 1 H), 3.38-3.43 (m, 1H), 3.37 (s, 3H), 3.30 (br d, J = 14.3 Hz, 1H), 2.96-3.04 (m, 2H), 2.85-2.94 (m, 2H), 2.77 -2.84 (m, 2H), 2.54-2.68 (m, 3H), 2.36-2.43 (m, 1H), 2.23-2.35 (m, 2H), 2.14-2.23 (m, 2H), 2.06 -2.14 (m, 2H), 1.83-2.03 (m, 4H), 1.50-1.76 (m, 4H), 1.35-1.47 (m, 10H), 1.05 (d, J = 6.7 Hz, 3H ). MS (ESI, cation) m / z 753.2 (M + H) ⁺ .

Example 6

(1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -7 '-((4-tert-butyl-1-piperazinyl) methyl) -6-chloro- 7'-ethoxy-11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-[20] oxa [13] thia [1,14] Diazatetracyclo [14.7.2.0 ~ 3,6 ~ .0 ~ 19,24 ~] Pentacosa [8,16,18,24] tetraene] -15'-one 13 ', 13'-dioxide

(1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-ethoxy-11 ', 12'-dimethyl-15' Oxo-3,4-dihydro-2H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diaza tetracyclo [14.7.2.0-3,6-0.0 ... 19,24 ~] pentacosa [8,16,18,24] tetraene] -7'-carbaldehyde 13 ', 13'-dioxide (0.035 g, 0.053 mmol), 1,2-dichloroethane (0.7 mL ) And N- t-butylpiperazine (0.026 mL, 0.160 mmol, Oakwood Products, Inc.) were added. The solution was stirred at rt for 30 min. To this solution was added sodium triacetoxyborohydride (2.83 mg, 0.013 mmol). The reaction was stirred at rt. After 1 hour, sodium triacetoxyborohydride (2.83 mg, 0.013 mmol) was further added every hour until the reaction was complete. The reaction was carefully quenched with MeOH, stirred for 30 minutes and then concentrated. Purification by silica gel chromatography (0% to 10% MeOH / CH ₂ Cl ₂ ) (1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -7 '-((4-tert-butyl-1-piperazinyl) methyl) -6-chloro-7'-ethoxy-11', 12'-dimethyl-3,4-dihydro-2H, 15'H Spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6-0.0-19,24-] pentacosa [8,16 , 18,24] tetraen] -15'-one 13 ', 13'-dioxide was obtained as a white solid (0.0284 g, 0.036 mmol, 68% yield). ¹ H NMR (400 MHz, Dichloromethane-d2) δ ppm 7.73 (d, J = 8.6 Hz, 1 H), 7.31 (s, 1 H), 7.16 (dd, J = 8.5, 2.2 Hz, 1 H) , 7.08 (d, J = 2.2 Hz, 1 H), 7.02 (br d, J = 8.0 Hz, 1 H), 6.84 (d, J = 8.2 Hz, 1 H), 5.55-5.74 (m, 2H) , 3.96-4.10 (m, 3H), 3.79 (br s, 1H), 3.69 (br d, J = 14.5 Hz, 1H), 3.50-3.65 (m, 1H), 3.34-3.45 (m, 1 H), 3.30 (d, J = 14.3 Hz, 1 H), 2.94-3.04 (m, 1 H), 2.73-2.80 (m, 2 H), 2.58-2.68 (m, 3 H), 2.45-2.57 (m, 3H), 2.29-2.35 (m, 1H), 2.03-2.18 (m, 4H), 1.90-1.98 (m, 2H), 1.81-1.90 (m, 2H), 1.55-1.70 (m, 3H), 1.45-1.53 (m, 1H), 1.34-1.44 (m, 1H), 1.24-1.31 (m, 9H), 1.17-1.24 (m, 9H), 1.00 (d , J = 6.8 Hz, 3 H). MS (ESI, cation) m / z 781.3 (M + H) ⁺ .

Example 7

(1S, 3'R, 6'R, 7'S, 11'S, 12'R) -6-chloro-7 '-((9aS) -hexahydropyrazino [2,1-c] [1,4] oxazine -8 (1H) -ylmethyl) -7'-hydroxy-11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-[20] Oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [16,18,24] triene] -15'-one 13 ' , 13'-dioxide

General Method 6 (Steps 1 and 2)

Step 1: (1S, 3'R, 6'R, 11'S, 12'R) -6-Chloro-11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-dispiro [ Naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [16,18,24] Triene-7 ', 2' '-oxirane] -15'-one 13', 13'-dioxide

(1S, 3'R, 6'R, 11'S, 12'R) -6-chloro-11 ', 12'-dimethyl-3,4-dihydro-2H, 7'H, in DMSO (1.5 mL), 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6-0.0-19,24-] pentacosa [ Hydroxide in a stirred solution of 16,18,24] triene] -7 ', 15'-dione 13', 13'-dioxide (100 mg, 0.167 mmol) and trimethylsulfonium iodine (38.6 mg, 0.175 mmol) Potassium (33.0 mg, 0.501 mmol) was added at room temperature. The resulting mixture was stirred at rt for 18 h. The mixture was poured into saturated aqueous ammonium chloride solution and extracted twice with EtOAc. The combined organics were dried over anhydrous sodium sulfate. The residue was separated by combi-flash column chromatography on a 12 g ISCO gold column eluting with 10% to 100% EtOAc / hexanes (1S, 3'R, 6'R, 11'S, 12'R) -6-chloro -11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-dispiro [naphthalene-1,22'-[20] oxa [13] thia [1,14] diatetracyclo [14.7.2.0 ~ 3,6 ~ .0 ~ 19,24 ~] Pentacosa [16,18,24] trien-7 ', 2''-oxirane]-15'-one13',13'- Dioxide was obtained as a diastereomeric mixture (72 mg, 0.117 mmol, 70% yield). MS (ESI, cation) m / z 613.1 (M + H) ⁺ .

Step 2: (1S, 3'R, 6'R, 7'S, 11'S, 12'R) -6-chloro-7 '-((9aS) -hexahydropyrazino [2,1-c] [1,4 ] Oxazine-8 (1H) -ylmethyl) -7'-hydroxy-11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'- [20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [16,18,24] triene] -15'- On 13 ', 13'-dioxide

(1S, 3'R, 6'R, 11'S, 12'R) -6-chloro-11 ', 12'-dimethyl-3,4-di in EtOH (6.0 mL) in a sealed microwave reaction vessel Hydro-2H, 15'H-dicespiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diaza tetraceclo [14.7.2.0-3,6 ~ .0 ~ 19, 24 ~] pentacosa [16,18,24] trien-7 ', 2''-oxirane]-15'-one13',13'-dioxide (840 mg, 1.37 mmol), (S) -octa A mixture of hydropyrazino [2,1-c] [1,4] oxazine dihydrochloride (1.47 g, 6.85 mmol), and triethylamine (3.00 mL, 21.6 mmol) was subjected to microwave reaction conditions (24 h, 90 ° C.). The crude mixture was added directly onto silica gel precolumn (25 g) and separated by combi-flash column chromatography on a 12 g ISCO gold column eluting with 0% to 20% MeOH / DCM to separate the two epimer beta-hydrates. An impure mixture of the loxylamine product was obtained, which was separated by SFC (Column: MSA, mobile phase: 65:35 (A: B) isocratic, A: liquid CO ₂ , B: methanol (20 mM NH ₃ ), flow rate : 70 g / min, column / oven temperature: 40 ° C., detection: UV at 240 nm). The first eluting epimer was collected on both reverse phase prep-HPLC and SFC columns, separated by combi-flash column chromatography on a 12 g ISCO gold column eluting with 0% to 20% MeOH / DCM (1S, 3'R). , 6'R, 7'S, 11'S, 12'R) -6-chloro-7 '-((9aS) -hexahydropyrazino [2,1-c] [1,4] oxazine-8 (1H)- Monomethyl) -7'-hydroxy-11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-[20] oxa [13] thia [ 1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [16,18,24] triene] -15'-on 13 ', 13'-dioxide Obtained as a white solid (340 mg, 0.45 mmol, 33% yield). ¹ H NMR (400 MHz, Dichloromethane-d2) δ 7.72 (d, J = 8.61 Hz, 1H), 7.17 (dd, J = 2.15, 8.41 Hz, 1H), 7.09 (d, J = 2.15 Hz, 1H ), 7.01 (s, 1H), 6.91-6.99 (m, 2H), 4.04-4.15 (m, 3H), 3.87 (br d, J = 15.06 Hz, 1H), 3.78 (dd, J = 2.93, 11.15 Hz , 1H), 3.69 (br d, J = 14.28 Hz, 1H), 3.56-3.65 (m, 2H), 3.16-3.27 (m, 2H), 3.00 (br dd, J = 8.71, 15.16 Hz, 1H), 2.87 (br d, J = 9.98 Hz, 1H), 2.59-2.79 (m, 7H), 2.44-2.54 (m, 3H), 2.23-2.41 (m, 4H), 1.98-2.12 (m, 3H), 1.87 -1.96 (m, 2H), 1.80-1.86 (m, 1H), 1.69-1.78 (m, 2H), 1.55 (br dd, J = 9.29, 13.79 Hz, 3H), 1.20-1.44 (m, 9H), 0.98 (d, J = 6.65 Hz, 3H). MS (ESI, cation) m / z 755.3 (M + H) ⁺ .

Example 8

(1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-methoxy-11 ', 12'-dimethyl-7'-(( (3R) -3-methyl-4- (1-methylethyl) -1-piperazinyl) methyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20 ] Oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraene] -15'- On 13 ', 13'-dioxide

Step 1: (R) -tert-butyl 4-isopropyl-3-methylpiperazin-1-carboxylate

A mixture of (R) -1-boc-3-methyl-piperazine (630 mg, 3.15 mmol) and acetone (3.0 mL, 40.9 mmol) in DCM (4.0 mL) was stirred for 10 minutes and sodium triacetoxyboro Hydride (1333 mg, 6.29 mmol) was added in one portion as a solid. The resulting mixture was stirred at rt for 2.5 days. MeOH (0.5 mL) was added to the reaction and the mixture was stirred for 5 minutes and then added directly to silica gel precolumn (25 g) and combi-flash on a 24 g gold column eluting with 2% to 20% MeOH / DCM. Separation by column chromatography gave (R) -tert-butyl 4-isopropyl-3-methylpiperazin-1-carboxylate as a colorless oil (0.72 g, 2.97 mmol, 94% yield). ¹ H NMR (400 MHz, Dichloromethane-d2) δ 3.54-3.90 (m, 2H), 3.25 (td, J = 6.41, 13.01 Hz, 1H), 3.02 (br s, 1H), 2.64-2.84 (m , 2H), 2.52-2.63 (m, 1H), 2.19-2.34 (m, 1H), 1.43 (s, 9H), 1.10 (d, J = 6.65 Hz, 3H), 1.04 (d, J = 6.26 Hz, 3H), 0.90 (d, J = 6.65 Hz, 3H). MS (ESI, cation) m / z 243.2 (M + H) ⁺ .

Step 2: (R) -1-Isopropyl-2-methylpiperazine Bis-TFA Salt

Trifluoroacetic acid (3.0 mL, 40 mmol) in a stirred solution of (R) -tert-butyl 4-isopropyl-3-methylpiperazin-1-carboxylate (670 mg, 2.76 mmol) in DCM (10 mL) Was added at room temperature. The resulting mixture was stirred at rt for 40 min. The volatiles were removed and the residue was treated with high vacuum to afford the (R) -1-isopropyl-2-methylpiperazine bis-TFA salt as an off-white solid. ¹ H NMR (400 MHz, Dichloromethane-d2) δ 11.33-12.07 (m, 2H), 10.45-11.02 (m, 1H), 3.88-4.10 (m, 3H), 3.72-3.86 (m, 2H), 3.49-3.65 (m, 3H), 1.46 (dd, J = 6.46, 12.91 Hz, 6H), 1.31 (d, J = 6.65 Hz, 3H). MS (ESI, cation) m / z 143.2 (M + H) ⁺ .

Step 3: (1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-methoxy-11 ', 12'-dimethyl-7' -(((3R) -3-methyl-4- (1-methylethyl) -1-piperazinyl) methyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 ' [20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraene]- 15'-on 13 ', 13'-dioxide

(1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-Chloro-7'-methoxy-11 ', 12'-dimethyl-15'-oxo- 3,4-Dihydro-2H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diaza tetracyclo [14.7.2.0-3,6-0.0-19,24 Pentacosa [8,16,18,24] tetraene] -7'-carbaldehyde 13 ', 13'-dioxide (20 mg, 0.031 mmol) and (R) -1-iso in DCM (1.5 mL) To a stirred mixture of propyl-2-methylpiperazine bis-TFA salt (76.2 mg, 0.206 mmol) was added N, N-diisopropylethylamine (0.50 mL, 2.9 mmol). The resulting mixture was stirred at room temperature for 10 minutes and sodium triacetoxyborohydride (26.4 mg, 0.125 mmol) was added in one portion as a solid. The resulting mixture was stirred at rt for 25 h. The reaction mixture was concentrated in vacuo and the residue dissolved in MeOH and taken up, preparative reversed phase HPLC (Gemini ™ Prep C ₁₈ 10 μm column; Phenomenex, Torrance, CA; gradient elution of 35% to 90% MeCN in water (two All solvents contain 0.1% TFA), a 15 minute gradient in a 24 minute process), followed by freeze drying (1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12 '). R) -6-chloro-7'-methoxy-11 ', 12'-dimethyl-7'-(((3R) -3-methyl-4- (1-methylethyl) -1-piperazinyl) Methyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] Pentacosa [8,16,18,24] tetraen] -15'-one 13 ', 13'-dioxide was obtained as a TFA salt of a white solid (17.6 mg, 0.020 mmol). , 64% yield). ¹ H NMR (400 MHz, Dichloromethane-d2) δ 8.08 (br s, 1H), 7.71 (d, J = 8.61 Hz, 1H), 7.11-7.20 (m, 2H), 7.09 (d, J = 1.76 Hz, 1H), 6.90 (s, 2H), 5.78-5.96 (m, 1H), 5.47 (br d, J = 15.65 Hz, 1H), 4.13-4.26 (m, 1H), 4.07 (s, 2H), 3.82-3.99 (m, 2H), 3.58-3.77 (m, 2H), 3.20-3.51 (m, 9H), 2.92-3.04 (m, 1H), 2.74-2.82 (m, 3H), 2.51-2.62 (m , 2H), 2.02-2.18 (m, 6H), 1.85-1.97 (m, 3H), 1.72-1.79 (m, 1H), 1.55-1.68 (m, 2H), 1.35-1.45 (m, 10H), 1.24 (d, J = 6.85 Hz, 3H), 1.02 (d, J = 6.65 Hz, 3H). MS (ESI, cation) m / z 767.2 (M + H) ⁺ .

Example 9

(1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-ethoxy-11 ', 12'-dimethyl-7'-(( (3R) -3-methyl-4- (1-methylethyl) -1-piperazinyl) methyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20 ] Oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraene] -15'- On 13 ', 13'-dioxide

General method 10

In one dram vial (1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-ethoxy-11 ', 12'- Dimethyl-15'-oxo-3,4-dihydro-2H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3, 6 ~ .0 ~ 19,24 ~] Pentacosa [8,16,18,24] tetraene] -7'-carbaldehyde 13 ', 13'-dioxide (12 mg, 0.018 mmol) was added, followed by DCM ( (R) -1-isopropyl-2-methylpiperazine 2,2,2-trifluoroacetate (46.9 mg, 0.126 mmol) and N, N-diisopropylethylamine (0.60 mL, 3.5 in 1.5 mL) mmol) was added. The resulting mixture was stirred at room temperature for 10 minutes and sodium triacetoxyborohydride (16 mg, 0.073 mmol) was added in one portion as a solid. The resulting mixture was stirred at rt for 58 h. The reaction mixture was concentrated in vacuo and the residue dissolved in MeOH and taken up, preparative reversed phase HPLC (Gemini ™ Prep C18 10 μm column; Phenomenex, Torrance, CA; gradient elution of 20% to 90% MeCN in water (two Solvents all contained 0.1% TFA), 15 minute gradient in a 24 minute process), and after freeze drying (1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) ) -6-chloro-7'-ethoxy-11 ', 12'-dimethyl-7'-(((3R) -3-methyl-4- (1-methylethyl) -1-piperazinyl) methyl ) -3,4-Dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diaza tetracyclo [14.7.2.0-3,6] .0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ', 13'-dioxide was obtained as a white solid TFA salt (11.2 mg, 0.013 mmol, 70% yield). ¹ H NMR (400 MHz, Dichloromethane-d2) δ 8.05 (br s, 1H), 7.71 (d, J = 8.61 Hz, 1H), 7.17 (dd, J = 2.25, 8.51 Hz, 1H), 7.08- 7.13 (m, 2H), 6.90 (s, 2H), 5.94-6.08 (m, 1H), 5.55-5.64 (m, 1H), 4.20-4.29 (m, 1H), 4.08 (s, 2H), 3.85- 3.92 (m, 2H), 3.70-3.83 (m, 2H), 3.62-3.68 (m, 1H), 3.46-3.58 (m, 3H), 3.33 (br d, J = 4.50 Hz, 2H), 3.26 (d , J = 14.28 Hz, 1H), 2.99 (br dd, J = 10.07, 14.57 Hz, 2H), 2.73-2.87 (m, 3H), 2.57 (br dd, J = 7.92, 14.18 Hz, 2H), 2.11- 2.18 (m, 3H), 2.06 (br d, J = 13.89 Hz, 2H), 1.86-1.98 (m, 4H), 1.79 (br d, J = 8.02 Hz, 1H), 1.67 (br d, J = 4.89 Hz, 2H), 1.37-1.45 (m, 13H), 1.24 (d, J = 6.65 Hz, 3H), 1.01 (d, J = 6.65 Hz, 3H). MS (ESI, cation) m / z 781.2 (M + H) ⁺ .

Example 10

(1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-methoxy-11 ', 12'-dimethyl-7'-(( 9AR) -octahydro-2H-pyrido [1,2-A] pyrazin-2-ylmethyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] Oxa [13] thia [1,14] diazetcyclocyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraene] -15'- On 13 ', 13'-dioxide

General Method 7 (Steps 1 and 2)

Step 1: (1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-11 ', 12'-dimethyl-7' -((9aR) -octahydro-2H-pyrido [1,2-a] pyrazin-2-ylmethyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'- [20] oxa [13] thia [1,14] diazetcyclocyclo [14.7.2.0-3,6-0.0-19,24-] pentacosa [8,16,18,24] tetraene]- 15'-on 13 ', 13'-dioxide

Preparation of the amine free base: In a 150 mL round bottom flask was prepared with (R) -octahydro-1H-pyrido [1,2-a] pyrazine dihydrochloride (5.0 g, 23.5 mmol, WuXi). Methanol (30 mL) was added. To the solution at room temperature sodium methoxide (25 wt% solution in methanol, 14.0 mL, 58.6 mmol) was added over 2 minutes. The solution was stirred at rt for 10 min and then concentrated. The material was treated with 2-methyltetrahydrofuran to form a suspension and then filtered. The filtrate was concentrated to form a viscous brown oil. The oil was treated with 2-methyltetrahydrofuran and heptane, filtered through a syringe filter and concentrated to give (R) -octahydro-1H-pyrido [1,2-a] pyrazine (3.4 g) as a brown semi-solid Obtained as.

In a 250 mL three neck flask (1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-11 ', 12'-dimethyl-3,4- Dihydro-2H, 15'H-dispiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6-0.0-19, 24 ~] pentacosa [8,16,18,24] tetraen-7 ', 2''-oxirane]-15'-one13',13'-dioxide (4.75 g, 7.77 mmol), sodium tert- Butoxide (1.49 g, 15.5 mmol), and 2-methyltetrahydrofuran (40 mL) were added. To the solution was added (R) -octahydro-1H-pyrido [1,2-a] pyrazine (1.64 g, 11.7 mmol). The reaction mixture was then heated at 65 ° C. for 1 day. The solution was cooled to room temperature and treated with pH 7 buffer ((K ₂ HPO ₄ / KH ₂ PO ₄ series). The solution was extracted with DCM (3 ×), the combined extracts were washed with water and brine, Na ₂ SO ₄ The crude product (1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-11 ', 12' -Dimethyl-7 '-((9aR) -octahydro-2H-pyrido [1,2-a] pyrazin-2-ylmethyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene -1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6-0.0-19,24-] pentacosa [8,16,18,24 ] Tetraen] -15'-on 13 ', 13'-dioxide was used as is to the next step.

Step 2: (1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-methoxy-11 ', 12'-dimethyl-7' -((9aR) -octahydro-2H-pyrido [1,2-a] pyrazin-2-ylmethyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'- [20] oxa [13] thia [1,14] diazetcyclocyclo [14.7.2.0-3,6-0.0-19,24-] pentacosa [8,16,18,24] tetraene]- 15'-on 13 ', 13'-dioxide

(1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-11 ', 12'-dimethyl-7'-(( 9aR) -octahydro-2H-pyrido [1,2-a] pyrazin-2-ylmethyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] Oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraen] -15'-one To a 250 mL flask containing 13 ', 13'-dioxide (5.8 g, 7.7 mmol) was added 2-methyltetrahydrofuran (80 mL). The solution was cooled to 0 ° C. and potassium bis (trimethylsilyl) amide (1 M in THF, 19.3 mL, 19.3 mmol) was added over 5 minutes. After stirring for 10 minutes at 0 ° C., iodomethane (1.44 mL, 23.2 mmol) was added in one portion. The solution was stirred at 0 ° C. for 2 hours and then additional potassium bis (trimethylsilyl) amide (4 mL) was added, stirred for 10 minutes and then additional iodine methane (0.48 mL). The solution was stirred at 0 ° C. for 1 h, then aqueous pH 7 buffer (KH ₂ PO ₄ / K ₂ HPO ₄ series) was added and the reaction mixture was allowed to warm to room temperature. The solution was extracted with DCM (3 ×) and the combined extracts were washed with brine, dried over Na ₂ SO ₄ and concentrated on silica. Purification by silica gel chromatography (10% to 60% EtOAc / heptane, then 5% to 10% MeOH / CH ₂ Cl ₂ ) (1S, 3'R, 6'R, 7'R , 8'E, 11'S, 12'R) -6-chloro-7'-methoxy-11 ', 12'-dimethyl-7'-((9aR) -octahydro-2H-pyrido [1,2 -a] pyrazin-2-ylmethyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6--0.19-24]] Pentacosa [8,16,18,24] tetraen] -15'-one 13 ', 13'-dioxide was obtained as an off-white solid ( 3.30 g, 4.31 mmol, 56% yield). ¹ H NMR (400 MHz, Dichloromethane-d2) δ ppm 7.72 (d, J = 8.6 Hz, 1 H), 7.26 (d, J = 1.4 Hz, 1 H), 7.17 (dd, J = 8.6, 2.2 Hz, 1H), 7.09 (d, J = 2.0 Hz, 1H), 6.92-6.99 (m, 1H), 6.89 (d, J = 8.0 Hz, 1H), 5.64 (dt, J = 15.7, 5.3 Hz, 1 H), 5.42 (br d, J = 16.4 Hz, 1 H), 4.07 (s, 2 H), 4.03 (br d, J = 7.2 Hz, 1 H), 3.98 (br d, J = 14.9 Hz, 1 H), 3.70 (br d, J = 14.3 Hz, 1 H), 3.34 (s, 3 H), 3.23-3.30 (m, 1 H), 3.06-3.22 (m, 2 H), 2.90 -3.01 (m, 1H), 2.74-2.81 (m, 2H), 2.65-2.73 (m, 2H), 2.52-2.62 (m, 4H), 2.28-2.35 (m, 1H), 2.16 -2.26 (m, 2H), 2.03-2.15 (m, 3H), 1.81-1.99 (m, 6H), 1.71-1.79 (m, 2H), 1.57-1.71 (m, 4H), 1.47 1.56 (m, 2H), 1.34-1.44 (m, 5H), 1.02 (d, J = 6.7 Hz, 3H). MS (ESI, cation) m / z 765.3 (M + H) ⁺ .

Example 11

(1S, 3'R, 6'R, 7'R, 8'E, 11'S, -11'R) -6-chloro-7 '-((9aS) -hexahydropyrazino [2,1-c] [1,4] oxazine-8 (1H) -ylmethyl) -7'-methoxy-12 '-(2-methoxyethyl) -11'-methyl-3,4-dihydro-2H, 15' H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6-0.0-19,24-] pentacosa [8, 16,18,24] tetraene] -15'-on 13 ', 13'-dioxide

General Method 1 (Steps 3-7) and General Method 11 (Step 11)

Step 1: (3R, 4S) -1-methoxy-N, N-bis (4-methoxybenzyl) -4-methylhept-6-ene-3-sulfonamide

Under nitrogen, a 2 L dry three necked flask equipped with a thermocouple and magnetic stir bar was added (S) -N, N-bis (4-methoxybenzyl) -2-methylpent-4-ene-1-sulfonamide ( 54 g, 134 mmol) and 300 mL of dry toluene. The solution was cooled (in acetone / dry ice bath) until the internal temperature reached -76 ° C. N-butyllithium solution (1.6 M in hexane, 100 mL, 161 mmol) was slowly added through the cannula under positive pressure nitrogen. The mixture was stirred at -78 ° C for 1 hour. Then 2-bromoethyl methyl ether (18.88 mL, 201 mmol) was slowly added via syringe. After addition, the bath at -78 ° C was placed in an ice bath. After a total of 105 minutes of reaction time, the reaction was quenched with saturated ammonium chloride at 0 ° C. The mixture was diluted with water and EtOAc and warmed to room temperature with stirring. The layers were separated and extracted with more EtOAc. The combined organic layers were washed with water and brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was further separated to give 20.4 g of (3R, 4S) -1-methoxy-N, N-bis (4-methoxybenzyl) -4-methylhept-6-ene-3-sulfonamide (44.2 mmol, 55% yield). MS (ESI, cation) m / z 484.0 (M + Na) ⁺ .

Step 2: (3R, 4S) -1-methoxy-4-methylhept-6-ene-3-sulfonamide

At 0 ° C., (3R, 4S) -1-methoxy-N, N-bis (4-methoxybenzyl) -4-methylhept-6-ene-3-sulfonamide (20.4 g) in DMC (221 mL) , 44.2 mmol) and anisole (48.0 mL, 442 mmol) were added dropwise through addition funnel with trifluoroacetic acid (164 mL, 2210 mmol). The solution was warmed to room temperature and stirred overnight. The reaction was concentrated in vacuo. The remaining material was partitioned between DCM and saturated aqueous sodium bicarbonate. The layers were separated and the aqueous layer was extracted with DCM. The combined organic extracts were washed with saturated aqueous sodium chloride and dried over sodium sulfate. The solution was filtered and concentrated in vacuo to afford crude. (3R, 4S) -1-methoxy-4-methylhept-6-ene-3-sulfonamide via purification by flash column chromatography on silica gel (eluting with 0% to 100% EtOAc in heptane). Was obtained as a pale yellow oil (9.85 g, 44.5 mmol, 101% yield). MS (ESI, cation) m / z 243.9 (M + Na) ⁺ .

Step 3: (S) -5-(((1R, 2R) -2-((S) -1-acetoxyallyl) cyclobutyl) methyl) -6'-chloro-3 ', 4,4', 5 Tetrahydro-2H, 2'H-spiro [benzo [b] [1,4] oxazepine-3,1'-naphthalene] -7-carboxylic acid

At room temperature, 4- (dimethylamino) pyridine (0.821 g, 6.72 mmol), 2-methyltetrahydrofuran (80 mL), tree, in a 1 L three-necked flask equipped with a thermometer and a magnetic stir bar were injected with nitrogen. (S) -6'-chloro-5-(((1R, 2R) in ethylamine (7.02 mL, 50.4 mmol), acetic anhydride (4.76 mL, 50.4 mmol), and 2-methyltetrahydrofuran (80 mL) -2-((S) -1-hydroxyallyl) cyclobutyl) methyl) -3 ', 4,4', 5-tetrahydro-2H, 2'H-spiro [benzo [b] [1,4] Oxazepin-3,1'-naphthalene] -7-carboxylic acid (15.72 g, 33.6 mmol) was added via cannula over 20 minutes (internal temperature rose from 20 ° C to 25 ° C during the addition). The reaction mixture was stirred at rt for 1.5 h. Water (40 mL) was added (internal temperature rose from 23 ° C. to 26 ° C.) followed by 1 M Na ₂ HPO _{4 (} 60 mL). Sodium hydroxide (1 M, 20 mL, 220 mmol) was added until the pH reached 9. The mixture was stirred at rt for 19 h and the pH was adjusted to 3 with 2 M HCl (80 mL). The mixture was diluted with PhMe (150 mL) and transferred to a separatory funnel. The aqueous layer was discarded and the organic phase was washed with water (75 mL) and 20% brine (75 mL) and concentrated under reduced pressure. The concentrate was diluted with PhMe (100 mL) and PhMe was removed under reduced pressure. Repeat this three times (S) -5-(((1R, 2R) -2-((S) -1-acetoxyallyl) cyclobutyl) methyl) -6'-chloro-3 ', 4,4' , 5-Tetrahydro-2H, 2'H-spiro [benzo [b] [1,4] oxazepine-3,1'-naphthalene] -7-carboxylic acid was obtained as an orange oil which was used without further purification. . MS (ESI, cation) m / z 510.2 (M + H) ⁺ .

Step 4: (S) -1-((1R, 2R) -2-(((S) -6'-chloro-7-((((3R, 4S) -1-methoxy-4-methylhept-) 6-en-3-yl) sulfonyl) carbamoyl) -3 ', 4'-dihydro-2H, 2'H-spiro [benzo [b] [1,4] oxazepine-3,1'-naphthalene ] -5 (4H) -yl) methyl) cyclobutyl) allyl acetate

Into a 1 L three-necked flask (S) -5-(((1R, 2R) -2-((S) -1-acetoxyallyl) cyclobutyl) methyl) -6'-chloro-3 ', 4, A solution of 4 ', 5-tetrahydro-2H, 2'H-spiro [benzo [b] [1,4] oxazepine-3,1'-naphthalene] -7-carboxylic acid (28.73 g, 35.8 mmol) in toluene As (228 mL). DMF (0.277 mL, 3.58 mmol) was added followed by the slow addition of thionyl chloride (2.74 mL, 37.6 mmol) via syringe. The reaction was stirred at rt for 4 h, additional thionyl chloride (0.50 mL) was added and the reaction stirred for 1 h. In separate flasks, (3R, 4S) -1-methoxy-4-methylhept-6-ene-3-sulfonamide (9.85 g, 42.5 mmol) and 4- (dimethylamino) pyridine (0.437 g, 3.58 mmol ) Were combined, concentrated in vacuo with PhMe (80 mL), azeotroped and dissolved in 100 mL of PhMe. The resulting solution was added via cannula to the acidic chloride solution described above. The solution was cooled in an ice bath for 10 minutes and then triethylamine (17.41 mL, 125 mmol) was added dropwise through an addition funnel. After addition, the reaction was allowed to warm to room temperature and stirred overnight. The reaction was quenched with saturated ammonium chloride. 0.1 M aqueous HCl was added to the mixture and then the mixture was extracted with EtOAc (3 ×). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. Purification by flash chromatography on silica gel (eluting with 0% to 100% EtOAc in heptane) (S) -1-((1R, 2R) -2-(((S) -6'-chloro -7-(((((3R, 4S) -1-methoxy-4-methylhept-6-en-3-yl) sulfonyl) carbamoyl) -3 ', 4'-dihydro-2H, 2' H-spiro [benzo [b] [1,4] oxazepine-3,1'-naphthalene] -5 (4H) -yl) methyl) cyclobutyl) allyl acetate (28.11 g, 39.4 mmol) was obtained as an orange foam. And used for the next step without further purification. MS (ESI, cation) m / z 713.0 (M + H) ⁺ .

Step 5: (1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-12 '-(2-methoxyethyl) -11'-methyl-13', 13'-dioxido-15'-oxo-3,4-dihydro-2H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazettracyclo [14.7. 2.0 ~ 3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraen] -7'-yl acetate

3.6 L of toluene was charged to a 5 L reactor equipped with a mechanical stirrer, thermocouple, nitrogen sparger, and condenser. PhMe was heated at 79 ° C. while sparging nitrogen through the solution. In a separate flask, (S) -1-((1R, 2R) -2-(((S) -6'-chloro-7-((((3R, 4S) -1-methoxy-4-methyl Hept-6-en-3-yl) sulfonyl) carbamoyl) -3 ', 4'-dihydro-2H, 2'H-spiro [benzo [b] [1,4] oxazepine-3,1' -Naphthalene] -5 (4H) -yl) methyl) cyclobutyl) allyl acetate (25.14 g, 32.0 mmol) was azeotrope mixed with 300 mL of toluene and then 1.2 L of PhMe was added via syringe pump for 2 hours. Diluted. At the same time, Umicore M73 SIMes (Umicore AG & Co. KG, Precious Metals Chemistry, Rodenbacher Chaussee 4, 63457 Hanau-Wolfgang, Germany) were added as a slurry in 5 mL of PhMe in 4 doses (4 x 238 mg). Each dose was added at 40 minute intervals. After 4 hours, the reaction was cooled to 30 ° C. and di (ethylene glycol) vinyl ether (0.350 mL, 2.56 mmol) was added and the solution was stirred overnight while sparging with nitrogen through a sparging tube replaced with a nitrogen inlet. The volume of reactant removed from the reactor was reduced to 1 L. SiliaMetS thiol (70 g) (SiliCycle Inc. 2500, Parc-Technologique Blvd, Quebec, Canada) was added and the mixture was stirred overnight. The mixture was filtered, SiliaMetS thiol was washed with EtOAc and the filtrate was concentrated. Purification by flash column chromatography on silica gel (330 g Gold Rf eluted with 0% to 100% EtOAc in heptane) (1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12 ' R) -6-chloro-12 '-(2-methoxyethyl) -11'-methyl-13', 13'-dioxide-15'-oxo-3,4-dihydro-2H-spiro [naphthalene-1 , 22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetra En] -7'-yl acetate was obtained as an orange oil (19.76 g, 28.8 mmol, 90% yield). MS (ESI, cation) m / z 685.0 (M + H) ⁺ .

Step 6: (1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-12 '-(2-methoxyethyl) -11' -Methyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diaza tetracyclo [14.7.2.0-3,6] ~ .0 ~ 19,24 ~] Pentacosa [8,16,18,24] tetraene] -15'-one 13 ', 13'-dioxide

(1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-12 '-(2-methoxyethyl) -11'-methyl- in toluene (100 mL) 13 ', 13'-dioxido-15'-oxo-3,4-dihydro-2H-spiro [naphthalene-1,22'-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0 ~ 3,6 ~ .0 ~ 19,24 ~] Pentacosa [8,16,18,24] tetraen] -7'-yl acetate (19.76 g, 24.83 mmol) and methanol (20.00 mL) To a solution of sodium methoxide (25% solution in methanol, 11.35 mL, 49.7 mmol) was added at room temperature. After 45 minutes, the reaction was quenched with citric acid (2 M aqueous solution, 37.2 mL, 74.5 mmol) and diluted with EtOAc and water. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic extracts were washed with saturated water (2 ×) and aqueous sodium chloride and dried over sodium sulfate. The mixture was filtered, concentrated in vacuo and dried overnight (1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-12'- (2-methoxyethyl) -11'-methyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diaza Tetracyclo [14.7.2.0 ~ 3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraen] -15'-one 13 ', 13'-dioxide as orange oil It was. MS (ESI, cation) m / z 643.0 (M + H) ⁺ .

Step 7: (1S, 3'R, 6'R, 8'E, 11'S, 12'R) -6-Chloro-12 '-(2-methoxyethyl) -11'-methyl-3,4-di Hydro-2H, 7'H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraene] -7 ', 15'-dione 13', 13'-dioxide

(1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-12 '-(2-methoxyethyl)-prepared in the previous step 11'-methyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3 , 6 ~ .0 ~ 19,24 ~] Pentacosa [8,16,18,24] tetraene] -15'-one 13 ', 13'-dioxide (19.1 g, 29.7 mmol) containing 1 L flask To DCM was added (300 mL). The solution was cooled in an ice bath for 20 minutes. Dess-Martin periodinan (15.11 g, 35.6 mmol) was added in one portion and the reaction stirred for 40 minutes while cooling in an ice bath. The reaction was removed from the ice bath and stirred at room temperature for 1.5 hours. Sodium thiosulfate was added followed by water and the mixture was vigorously stirred for 20 minutes. The reaction was diluted with saturated aqueous sodium bicarbonate and extracted three times with EtOAc. The combined organic layers were washed with water and brine, dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography (eluting with 0% to 60% EtOAc in heptanes) (1S, 3'R, 6'R, 8'E, 11'S, 12'R) -6-chloro-12'- (2-methoxyethyl) -11'-methyl-3,4 ', 13'-dihydro-2H, 7'H, 15'H-spiro [naphthalene-1,22'-[20] oxa [13] Thia [1,14] diaza tetracyclo [14.7.2.0-3,6-0.0-19,24-] pentacosa [8,16,18,24] tetraene] -7 ', 15'-dione 13 ', 13'-dioxide was obtained as an orange solid (14.29 g, 22.3 mmol, 75% yield). MS (ESI, cation) m / z 640.8 (M + H) ⁺ .

Step 8: (1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7 '-(1,3-dithiane-2-yl) -7 '-Hydroxy-12'-(2-methoxyethyl) -11'-methyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] Thia [1,14] diaza tetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraen] -15'-one 13 ', 13 '-Dioxide

To a 100 mL round bottom flask was added 1,3-dithiane (2.025 g, 16.84 mmol) in THF (42.1 mL). At -78 ° C, n-butyllithium (2.5 M solution in hexanes, 5.90 mL, 14.7 mmol) was added to the solution. The solution was stirred for 15 minutes and then (1S, 3'R, 6'R, 8'E, 11'S, 12'R) -6-chloro-12 '-(2-methoxyethyl) in 10 mL of THF. -11'-methyl-3,4 ', 13'-dihydro-2H, 7'H, 15'H-spiro [naphthalene-1,22'-[20] oxa [13] thia [1,14] dia Zatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] Pentacosa [8,16,18,24] tetraene] -7 ', 15'-dione 13', 13'-dioxide (2.70 g, 4.21 mmol) was added slowly. The mixture was stirred for 1 hour and 10 mL of saturated ammonium chloride was added to quench the reaction. The mixture was diluted with 1 N HCl (20 mL) and extracted with EtOAc (3 Х 40 mL). The organic extract was washed with saturated NaCl (40 mL) and dried over MgSO ₄ . The solution was filtered and concentrated in vacuo. Purification of the material (1S, 3 ') via chromatography (eluted using EtOAc in heptane with 0.1% HOAc) in a gradient of 0% to 60% via a redi-Sep prefilled silica gel column (80 g) R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7 '-(1,3-dithiane-2-yl) -7'-hydroxy-12'- (2-methoxyethyl) -11'-methyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diaza Tetracyclo [14.7.2.0-3,6 ~ .0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ', 13'-dioxide was obtained (1.6 g, 2.1 mmol, 50% yield). MS (ESI, cation) m / z 761.1 (M + H) ⁺ .

Step 9: (1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7 '-(1,3-ditian-2-yl) -7 '-Methoxy-12'-(2-methoxyethyl) -11'-methyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] Thia [1,14] diaza tetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraen] -15'-one 13 ', 13 '-Dioxide

In a 100 mL round-bottom flask (1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7 '-(1,3) in THF (21 mL) -Ditian-2-yl) -7'-hydroxy-12 '-(2-methoxyethyl) -11'-methyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1, 22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6-0.0-19,24-] pentacosa [8,16,18,24] tetraene ] -15'-one 13 ', 13'-dioxide (1.6 g, 2.1 mmol) and iomethane (1.044 mL, 16.81 mmol) were added. At 0 ° C., sodium hydride (0.504 g, 21.0 mmol) was added once. The reaction was stirred at rt for 5 h. The reaction mixture was diluted with saturated NH ₄ Cl (20 mL) and extracted twice with EtOAc (20 mL). The combined organic extracts were washed with saturated NaCl (15 mL) and dried over MgSO ₄ . The solution was filtered and concentrated in vacuo. Via purification by preparative silica gel column of Redi-Sep (40 g) eluting with EtOAc in heptanes (containing 0.1% HOAc) in a gradient of 0% to 60% (1S, 3 'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-(1,3-dithiane-2-yl) -7'-methoxy-12 ' -(2-methoxyethyl) -11'-methyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] dia Zatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] Pentacosa [8,16,18,24] tetraen] -15'-one 13 ', 13'-dioxide as off-white solid Obtained (0.93 g, 1.2 mmol, 57% yield). MS (ESI, cation) m / z 775.1 (M + H) ⁺ .

Step 10: (1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-Chloro-7'-methoxy-12 '-(2-methoxyethyl)- 11'-methyl-15'-oxo-3,4-dihydro-2H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0 ~ 3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraene] -7'-carbaldehyde 13 ', 13'-dioxide

(1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7 '-(1,3-dithiane-2-yl) -7 in a removable vial '-Methoxy-12'-(2-methoxyethyl) -11'-methyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] Thia [1,14] diaza tetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraene] -15'-one 13 ', 13 '-Dioxide (0.93 g, 1.2 mmol), acetonitrile (9.6 mL) and water (2.4 mL) were added. To the mixture was added calcium carbonate (0.600 g, 6.00 mmol) and iodine methane (0.745 mL, 12.0 mmol). The mixture was heated at 45 ° C. overnight. The solution was poured into saturated NH ₄ Cl and water and extracted with EtOAc. The combined extracts were washed with brine then dried over Na ₂ SO ₄ and concentrated. Purification by silica gel chromatography (eluting with 0% to 60% EtOAc in heptanes containing 0.1% AcOH) (1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12 'R) -6-chloro-7'-methoxy-12'-(2-methoxyethyl) -11'-methyl-15'-oxo-3,4-dihydro-2H-spiro [naphthalene-1, 22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6-0.0-19,24-] pentacosa [8,16,18,24] tetraene ] -7'-carbaldehyde 13 ', 13'-dioxide was obtained as a white solid (0.70 g, 1.021 mmol, 85% yield). MS (ESI, cation) m / z 685.1 (M + H) ⁺ .

Step 11: (1S, 3'R, 6'R, 7'R, 8'E, 11'S, -11'R) -6-chloro-7 '-((9aS) -hexahydropyrazino [2,1 -c] [1,4] oxazine-8 (1H) -ylmethyl) -7'-methoxy-12 '-(2-methoxyethyl) -11'-methyl-3,4-dihydro-2H , 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6-0.0-19,24-] pentacosa [8,16,18,24] tetraene] -15'-on 13 ', 13'-dioxide

In a 100 mL round-bottom flask (1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-methoxy-12 in DCM (13.1 mL) '-(2-methoxyethyl) -11'-methyl-15'-oxo-3,4-dihydro-2H-spiro [naphthalene-1,22'-[20] oxa [13] thia [1,14 ] Diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraene] -7'-carbaldehyde 13 ', 13'-dioxide ( 450 mg, 0.657 mmol), (S) -octahydropyrazino [2,1-c] [1,4] oxazine HCl salt (1130 mg, 5.25 mmol) and N, N-diisopropylethylamine (2.341 mL, 13.13 mmol) was added. Titanium (IV) isopropoxide (0.770 mL, 2.63 mmol) was slowly added to the solution. The reaction was stirred at rt overnight. To the reaction was added sodium triacetoxyborohydride (278 mg, 1.31 mmol) once and the mixture was stirred overnight. The reaction was diluted with saturated NaCl (20 mL). The white precipitate was removed by filtration through celite. The filtrate was concentrated, diluted with 1 N HCl (20 mL) and extracted with EtOAc (3 Х 50 mL). The combined organic extracts were washed with saturated NaCl (50 mL) and dried over MgSO ₄ . The solution was filtered and concentrated in vacuo. The concentrate was absorbed onto a silica gel plug and purified by chromatography via Redi-Sep's prefilled silica gel column (40 g, with a titanium bicarbonate layer on top). Eluting with methanol in DCM (0% to 10% gradient) to (1S, 3'R, 6'R, 7'R, 8'E, 11'S, -11'R) -6-chloro-7 '-(( 9aS) -hexahydropyrazino [2,1-c] [1,4] oxazine-8 (1H) -ylmethyl) -7'-methoxy-12 '-(2-methoxyethyl) -11' -Methyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diaza tetracyclo [14.7.2.0-3,6] ~ .0 ~ 19,24 ~] Pentacosa [8,16,18,24] tetraen] -15'-one 13 ', 13'-dioxide was obtained as a white solid (420 mg, 0.518 mmol, 79%). yield). MS (ESI, cation) m / z 811.0 (M + H) ⁺ . 1 H NMR (400 MHz, Dichloromethane-d2) δ ppm 0.91-1.10 (m, 3H), 1.33-1.72 (m, 10H, residual moisture), 1.81-1.97 (m, 5H), 2.03- 2.39 (m, 10 H), 2.41-2.69 (m, 6 H), 2.71-2.83 (m, 2 H), 2.90-3.08 (m, 2 H), 3.12-3.27 (m, 2 H), 3.33 ( s, 3 H), 3.37 (s, 3 H), 3.53-3.83 (m, 6 H), 3.95-4.09 (m, 3 H), 4.11-4.22 (m, 1 H), 5.23-5.29 (m, 1 H), 5.55-5.62 (m, 1 H), 6.80-6.93 (m, 2 H), 7.09 (s, 1 H), 7.13-7.22 (m, 1 H), 7.30 (s, 1 H), 7.72 (d, J = 8.41 Hz, 1 H).

Example 12

(1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-Chloro-7'-methoxy-12 '-(2-methoxyethyl) -11'- Methyl-7 '-(((3R) -3-methyl-4- (1-methylethyl) -1-piperazinyl) methyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene- 1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] Tetraene] -15'-one 13 ', 13'-dioxide

In a 25 mL flask, (1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-methoxy-12'- in DCM (2335 μL) (2-methoxyethyl) -11'-methyl-15'-oxo-3,4-dihydro-2H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] dia Zatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] Pentacosa [8,16,18,24] tetraene] -7'-carbaldehyde 13 ', 13'-dioxide (80 mg , 0.117 mmol), (R) -1-isopropyl-2-methylpiperazine bis (2,2,2-trifluoroacetate) (330 mg, 0.891 mmol), N, N-diisopropylethylamine ( 366 μL, 2.10 mmol) and titanium (IV) isopropoxide (137 μL, 0.467 mmol) were added. The solution was stirred at rt overnight. To this solution was added sodium triacetoxyborohydride (99 mg, 0.47 mmol). The reaction was stirred for 24 hours. The reaction mixture was diluted with 1 N HCl (10 mL) and extracted twice with DCM (20 mL). The organic solvent was concentrated. Purify the residue by prep-HPLC (1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-methoxy-12 '-( 2-methoxyethyl) -11'-methyl-7 '-(((3R) -3-methyl-4- (1-methylethyl) -1-piperazinyl) methyl) -3,4-dihydro- 2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6-0.0-19,24-] penta Cosa [8,16,18,24] tetraen] -15'-one 13 ', 13'-dioxide was obtained as a TFA salt. MS (ESI, cation) m / z 811.2 (M + H) ⁺ . ¹ H NMR (400 MHz, MeOH-d ₄ ) δ ppm 1.06 (d, J = 6.06 Hz, 3H), 1.25-1.48 (m, 10H), 1.49-2.30 (m, 12H), 2.42-2.84 (m, 8H), 2.94-3.27 (m, 4H), 3.35 (s, 3H), 3.42 (s, 4H), 3.51-3.74 (m, 5H), 3.91-4.10 (m, 3 H), 4.14-4.25 (m, 1H), 5.35 (d, J = 16.04 Hz, 1H), 5.69-5.82 (m, 1H), 6.86-6.94 (m, 1H), 7.01 (dd, J = 8.02, 1.76 Hz, 1 H), 7.10 (d, J = 1.96 Hz, 1 H), 7.16 (dd, J = 8.41, 2.15 Hz, 1 H), 7.26 (d, J = 1.37 Hz, 1 H ), 7.73 (d, J = 8.61 Hz, 1H).

Example 13

(1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-Chloro-7'-ethoxy-7 '-((9aS) -hexahydropyrazino [2 , 1-c] [1,4] oxazine-8 (1H) -ylmethyl) -12 '-(2-methoxyethyl) -11'-methyl-3,4-dihydro-2H, 15'H Spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6-0.0-19,24-] pentacosa [8,16 , 18,24] tetraene] -15'-on 13 ', 13'-dioxide

Step 1: (1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7 '-(1,3-dithiane-2-yl) -7 '-Ethoxy-12'-(2-methoxyethyl) -11'-methyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] Thia [1,14] diaza tetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraen] -15'-one 13 ', 13 '-Dioxide

In a 100 mL round bottom flask was placed (1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro- in N, N-dimethylformamide (8.14 mL). 7 '-(1,3-dithiane-2-yl) -7'-hydroxy-12'-(2-methoxyethyl) -11'-methyl-3,4-dihydro-2H, 15'H Spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6-0.0-19,24-] pentacosa [8,16 , 18,24] tetraen] -15'-one 13 ', 13'-dioxide (0.62 g, 0.814 mmol) and iodine methane (0.655 mL, 8.14 mmol) were added. At 0 ° C., potassium bis (trimethylsilyl) amide (1 M in THF, 8.14 mL, 8.14 mmol) was added slowly. The reaction was stirred overnight. The reaction mixture was diluted with 1 N HCl (15 mL) and extracted with EtOAc (3 Х 15 mL). The organic extract was washed with saturated NaCl (15 mL) and dried over MgSO ₄ . The solution was filtered and concentrated in vacuo. The concentrate was taken up on a silica gel plug and purified by chromatography (eluted with EtOAc in heptane (containing 0.1% HOAc) in a gradient of 0% to 60%) via 24 g ISCO gold column (1S , 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7 '-(1,3-dithiane-2-yl) -7'-ethoxy- 12 '-(2-methoxyethyl) -11'-methyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-[20] oxa [13] thia [1,14 ] Diazatetracyclo [14.7.2.0-3,6-0.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ', 13'-dioxide obtained (0.24 g, 0.304 mmol, 37% yield). MS (ESI, cation) m / z 789.1 (M + H) ⁺ .

Step 2: (1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-Chloro-7'-ethoxy-12 '-(2-methoxyethyl)- 11'-methyl-15'-oxo-3,4-dihydro-2H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0 ~ 3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraene] -7'-carbaldehyde 13 ', 13'-dioxide

In a removable vial (1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7 '-(1,3-dithiane-2-yl) -7 '-Ethoxy-12'-(2-methoxyethyl) -11'-methyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] Thia [1,14] diaza tetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraen] -15'-one 13 ', 13 '-Dioxide (510 mg, 0.646 mmol), acetonitrile (5168 μL) and water (1292 μL) were added. To the mixture was added calcium carbonate (323 mg, 3.23 mmol) and iodine methane (401 μL, 6.46 mmol). The mixture was heated at 45 ° C. overnight. The reaction was diluted with NH ₄ Cl (10 mL) and extracted with EtOAc (3 Х 15 mL). The combined organic extracts were washed with saturated NaCl (20 mL) and dried over MgSO ₄ . The solution was filtered and concentrated in vacuo. The concentrate was absorbed onto a silica gel plug and chromatographed via Redi-Sep's pre-filled silica gel column (40 g) eluted using EtOAc (containing 0.1% HOAc) in a gradient of 0% to 60%). Purification to (1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-ethoxy-12 '-(2-methoxyethyl) -11 '-Methyl-15'-oxo-3,4-dihydro-2H-spiro [naphthalene-1,22'-[20] oxa [13] thia [1,14] diaza tetracyclo [14.7.2.0-3] , 6 ~ .0 ~ 19,24 ~] Pentacosa [8,16,18,24] tetraene] -7'-carbaldehyde 13 ', 13'-dioxide was obtained as a white solid (230 mg, 0.329 mmol) , 50.9% yield). MS (ESI, cation) m / z 699.1 (M + H) ⁺ .

Step 3: (1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-ethoxy-7 '-((9aS) -hexahydropyra Gino [2,1-c] [1,4] oxazine-8 (1H) -ylmethyl) -12 '-(2-methoxyethyl) -11'-methyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6-0.0-19,24-] pentacosa [ 8,16,18,24] tetraene] -15'-on 13 ', 13'-dioxide

In a 50 mL round bottom flask (1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-ethoxy-12 '-(2-meth) Methoxyethyl) -11'-methyl-15'-oxo-3,4-dihydro-2H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatracyclo [ 14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraene] -7'-carbaldehyde 13 ', 13'-dioxide (150 mg, 0.215 mmol) , N, N-diisopropylethylamine (574) in (S) -octahydropyrazino [2,1-c] [1,4] oxazine HCl salt (277 mg, 1.29 mmol) and DCM (4290 μL) μL, 3.22 mmol) was added. The reaction was stirred at rt overnight. Sodium triacetoxyborohydride (182 mg, 0.858 mmol) was added to the reaction mixture. The reaction was stirred for 8 hours. The reaction mixture was diluted with 1 N HCl (20 mL) and extracted twice with DCM (20 mL). The organic layer was concentrated completely. The residue was further purified by prep_HPLC. The solution after pre-HPLC was washed with a solution of pH 7 and extracted twice with EtOAc (20 mL). The organic extract was washed with saturated NaCl (20 mL) and dried over MgSO ₄ . The solution was filtered and concentrated in vacuo to give (1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-ethoxy-7 '-((9aS ) -Hexahydropyrazino [2,1-c] [1,4] oxazine-8 (1H) -ylmethyl) -12 '-(2-methoxyethyl) -11'-methyl-3,4- Dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazettracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 Pentacosa [8,16,18,24] tetraen] -15'-one 13 ', 13'-dioxide was obtained as a white solid. MS (ESI, cation) m / z 825.2 (M + H) ⁺ . ¹ H NMR (400 MHz, Dichloromethane-d2) δ ppm 1.01 (d, J = 6.26 Hz, 3 H), 1.35 (t, J = 6.85 Hz, 3 H), 1.44-1.74 (m, 7 H) , 1.77-2.01 (m, 5 H), 2.04-2.38 (m, 9 H), 2.41-2.65 (m, 5 H), 2.70-2.83 (m, 2 H), 2.86-3.08 (m, 2 H) , 3.27 (d, J = 14.28 Hz, 1 H), 3.35 (s, 3 H), 3.40-3.49 (m, 1 H), 3.52-3.83 (m, 7 H), 3.99-4.10 (m, 3 H ), 4.12-4.28 (m, 1 H), 5.35-5.42 (m, 1 H), 5.57-5.76 (m, 1 H), 6.85-6.92 (m, 2 H), 7.09 (d, J = 2.15 Hz , 1H), 7.13-7.20 (m, 1H), 7.24 (s, 1H), 7.72 (d, J = 8.41 Hz, 1H).

Example 14

(1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-Chloro-7'-ethoxy-12 '-(2-methoxyethyl) -11'- Methyl-7 '-((4- (3-oxetanyl) -1-piperazinyl) methyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-[20 ] Oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraene] -15'- On 13 ', 13'-dioxide

General method 12

In a 25 mL flask, (1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-methoxy-12'- in DCM (3718 μL) (2-methoxyethyl) -11'-methyl-15'-oxo-3,4-dihydro-2H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] dia Zatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] Pentacosa [8,16,18,24] tetraene] -7'-carbaldehyde 13 ', 13'-dioxide (130 mg , 0.186 mmol) was added. To this solution was added 1- (oxetan-3-yl) piperazine (159 mg, 1.12 mmol) and one drop of acetic acid. The mixture was stirred for 8 hours and sodium triacetoxyborohydride (158 mL, 0.744 mmol) was added. The reaction was stirred for 2 hours, diluted with 1 N HCl (10 mL) and extracted three times with DCM (15 mL). The organic layer was concentrated. The concentrate was purified by prep_HPLC. The solution after prep-HPLC was washed with buffer at pH 7 and extracted with EtOAc. The organic layer was concentrated to (1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-ethoxy-12 '-(2-methoxyethyl) -11'-methyl-7 '-((4- (3-oxetanyl) -1-piperazinyl) methyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraene -15'-one 13 ', 13'-dioxide was obtained as a white solid. MS (ESI, cation) m / z 825.2 (M + H) ⁺ . ¹ H NMR (400 MHz, Dichloromethane-d2) δ ppm 0.98 (br s, 3 H), 1.29-1.43 (m, 4 H), 1.47-2.24 (m, 12 H), 2.24-2.41 (m, 4 H), 2.45-2.84 (m, 9 H), 2.87-3.07 (m, 1 H), 3.27 (br d, J = 14.09 Hz, 1 H), 3.34 (s, 3 H), 3.39-3.52 ( m, 2H), 3.57-3.76 (m, 4H), 3.95-4.20 (m, 4H), 4.45-4.55 (m, 2H), 4.57-4.65 (m, 2H), 5.38-5.51 ( m, 1H), 5.59-5.74 (m, 1H), 6.89 (s, 2H), 7.09 (d, J = 1.96 Hz, 1H), 7.13-7.19 (m, 1H), 7.21-7.28 (m, 1H), 7.72 (d, J = 8.41 Hz, 1H).

Example 15

(1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-Chloro-7'-ethoxy-12 '-(2-methoxyethyl) -11'- Methyl-7 '-((9aR) -octahydro-2H-pyrido [1,2-a] pyrazin-2-ylmethyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1 , 22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetra EN] -15'-one 13 ', 13'-dioxide

In a 25 mL flask, (1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-ethoxy-12'- in DCM (1716 μL) (2-methoxyethyl) -11'-methyl-15'-oxo-3,4-dihydro-2H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] dia Zatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] Pentacosa [8,16,18,24] tetraene] -7'-carbaldehyde 13 ', 13'-dioxide (120 mg , 0.858 mmol) was added. One drop of acetic acid was added. The solution was stirred overnight at room temperature. To this solution was added sodium triacetoxyborohydride (73 mg, 0.34 mmol). The reaction was stirred for 8 h, diluted with 1 N HCl (10 mL) and extracted twice with DCM (10 mL). The solvent was removed under reduced pressure. Purify the concentrate by prep-HPLC (1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-ethoxy-12 '-(2 -Methoxyethyl) -11'-methyl-7 '-(((9aR) -octahydro-2H-pyrido [1,2-a] pyrazin-2-ylmethyl) -3,4-dihydro-2H , 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6-0.0-19,24-] pentacosa [8,16,18,24] tetraene; -15'- on a 13 ', 13'- dioxide was obtained as a TFA salt. MS (ESI, positive ions) m / z 823.2 (m + H) +. 1 H NMR (400 MHz, MeOH-d ₄ ) δ ppm 1.05 (d, J = 6.46 Hz, 3H), 1.37 (t, J = 6.85 Hz, 3H), 1.41-2.02 (m, 14H), 2.04- 2.26 (m, 5H), 2.30-2.51 (m, 2H), 2.51-2.87 (m, 6H), 2.92-3.08 (m, 3H), 3.11-3.26 (m, 2H), 3.35- 3.54 (m, 7H), 3.60-3.78 (m, 4H), 3.94-4.11 (m, 3H), 4.18-4.29 (m, 1H), 5.43 (d, J = 16.04 Hz, 1H) , 5.67-5.89 (m, 1H), 6.87-6.94 (m, 1H), 6.95-7.03 (m, 1H), 7.10 (d, J = 1.96 Hz, 1H), 7.14-7.19 (m, 1 H), 7.24 (d, J = 1.56 Hz, 1 H), 7.73 (d, J = 8.61 Hz, 1 H).

Example 16

(1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-Chloro-7'-ethoxy-12 '-(2-methoxyethyl) -11'- Methyl-7 '-((4- (1-methylethyl) -1-piperazinyl) methyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-[20] Oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraen] -15'-one 13 ', 13'-dioxide

In a 10 mL flask, (1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-methoxy-12'- in DCM (1716 μL) (2-methoxyethyl) -11'-methyl-15'-oxo-3,4-dihydro-2H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] dia Zatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] Pentacosa [8,16,18,24] tetraene] -7'-carbaldehyde 13 ', 13'-dioxide (60 mg , 0.086 mmol) was added. One drop of acetic acid was added and the reaction stirred overnight. Sodium triacetoxyborohydride (72.7 mg, 0.343 mmol) was added to the reaction mixture. The reaction was stirred at rt for 8 h. The reaction mixture was diluted with 1 N HCl (5 mL) and extracted twice with DCM (10 mL). The organic layer was concentrated. Purify the concentrate by prep-HPLC (1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-ethoxy-12 '-(2 -Methoxyethyl) -11'-methyl-7 '-((4- (1-methylethyl) -1-piperazinyl) methyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene -1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6-0.0-19,24-] pentacosa [8,16,18,24 ] Tetraen] -15'-one 13 ', 13'-dioxide was obtained as the TFA salt. MS (ESI, cation) m / z 811.2 (M + H) ⁺ . ¹ H NMR (400 MHz, MeOH-d4) δ ppm 1.05 (d, J = 6.46 Hz, 3 H), 1.29-1.47 (m, 10 H), 1.52-2.30 (m, 12 H), 2.51-2.87 ( m, 8H), 2.93-3.11 (m, 2H), 3.38 (s, 4H), 3.45-3.57 (m, 3H), 3.59-3.78 (m, 4H), 3.95-4.11 (m, 3 H), 4.20-4.33 (m, 1 H), 5.45 (d, J = 15.85 Hz, 1 H), 5.77-5.91 (m, 1 H), 6.84-6.94 (m, 1 H), 6.96-7.02 (m, 1H), 7.10 (d, J = 1.96 Hz, 1H), 7.16 (br d, J = 8.41 Hz, 1H), 7.23 (d, J = 1.57 Hz, 1H), 7.73 (d , J = 8.41 Hz, 1 H).

Example 17

(1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-Chloro-7'-ethoxy-12 '-(2-methoxyethyl) -11'- Methyl-7 '-(((3R) -3-methyl-4- (1-methylethyl) -1-piperazinyl) methyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene- 1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] Tetraene] -15'-one 13 ', 13'-dioxide

In a 25 mL flask, (1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-ethoxy-12'- in DCM (2288 μL). (2-methoxyethyl) -11'-methyl-15'-oxo-3,4-dihydro-2H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] dia Zatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] Pentacosa [8,16,18,24] tetraene] -7'-carbaldehyde 13 ', 13'-dioxide (80 mg , 0.11 mmol), (R) -1-isopropyl-2-methylpiperazin bis (2,2,2-trifluoroacetate) (254 mg, 0.686 mmol), N, N-diisopropylethylamine ( 408 μL, 2.29 mmol) and titanium (IV) isopropoxide (134 μL, 0.458 mmol) were added. The solution was stirred at rt for 8 h. To this solution was added sodium triacetoxyborohydride (97 mg, 0.46 mmol). The reaction was stirred overnight. The reaction mixture was diluted with 1 N HCl (10 mL) and extracted with DCM (2 Х 10 mL). The solvent was concentrated. Purify the residue by prep-HPLC (1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-ethoxy-12 '-( 2-methoxyethyl) -11'-methyl-7 '-(((3R) -3-methyl-4- (1-methylethyl) -1-piperazinyl) methyl) -3,4-dihydro- 2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6-0.0-19,24-] penta Cosa [8,16,18,24] tetraen] -15'-one 13 ', 13'-dioxide was obtained as a TFA salt. MS (ESI, cation) m / z 825.4 (M + H) ⁺ . ¹ H NMR (400 MHz, MeOH-d ₄ ) δ ppm 1.05 (d, J = 6.46 Hz, 3 H), 1.21-1.49 (m, 13 H), 1.51-2.28 (m, 12 H), 2.37-2.87 (m, 8H), 2.92-3.20 (m, 3H), 3.36-3.57 (m, 7H), 3.60-3.79 (m, 4H), 3.97-4.07 (m, 3H) 4.20-4.31 ( m, 1H), 5.43 (d, J = 16.04 Hz, 1H), 5.75-5.90 (m, 1H), 6.87-6.94 (m, 1H), 6.98-7.01 (m, 1H), 7.10 (d, J = 1.37 Hz, 1 H), 7.14-7.19 (m, 1 H), 7.24 (d, J = 1.37 Hz, 1 H), 7.73 (d, J = 8.61 Hz, 1 H).

Example 18

(1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7 '-((9aS) -hexahydropyrazino [2,1-c] [1, 4] oxazine-8 (1H) -ylmethyl) -7'-methoxy-11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22' -[20] oxa [13] thia [1,14,25] triazatetracyclo [14.7.2.0-3,6-0.0-19,24-] pentacosa [8,16,18,24] tetraene ] -15'-one 13 ', 13'-dioxide

General Method 2 (Steps 10-12) and General Method 4 (Steps 13-14)

Step 1: (S, E)-(6-Chloro-1-((hydroxyimino) methyl) -1,2,3,4-tetrahydronaphthalen-1-yl) methyl 4-bromobenzoate

(R)-(6-Chloro-1-formyl-1,2,3,4-tetrahydronaphthalen-1-yl) methyl 4-bromobenzoate (425 g, 1042 mmol) in DCM (5100 mL) Pyridine (337 mL, 4170 mmol) was added to a stirred solution of MeOH (5100 mL) under nitrogen atmosphere followed by hydroxylamine hydrochloride (145 g, 2085 mmol). The reaction mixture was stirred at rt for 3 h. The reaction was diluted with DCM (2.0 L) and the organic layer was washed with water (2.0 L). The organic layer was dried over calcium sulfate, filtered and concentrated under reduced pressure to afford (S, E)-(6-chloro-1-((hydroxyimino) methyl) -1,2,3,4-tetrahydronaphthalene-1 -Yl) methyl 4-bromobenzoate was obtained as a yellow liquid. The material was used for next step without further purification. ¹ H NMR (400 MHz, Chloroform-d) δ 7.85-7.80 (dd, J = 8.7, 2.1 Hz, 2H), 7.58-7.55 (m, 2H), 7.51 (s, 1H), 7.23-7.26 (m, 1H), 7.14-7.16 (m, 2H), 4.66-4.64 (d, J = 11.3 Hz, 1H), 4.56-4.53 (d, J = 11.2 Hz, 1H), 2.84-2.81 (t, J = 6.3 Hz , 2H), 2.14-2.02 (dddd, J = 14.8, 13.2, 7.1, 3.8 Hz, 2H), 1.96-1.83 (dddt, J = 13.9, 11.8, 5.9, 3.7 Hz, 2H).

Step 2: (S)-(1- (aminomethyl) -6-chloro-1,2,3,4-tetrahydronaphthalen-1-yl) methanol hydrochloride

(S, E)-(6-chloro-1-((hydroxyimino) methyl) -1,2,3,4-tetrahydronaphthalen-1-yl) methyl 4-bromobenzoate prepared in the previous step (425 g, 1005 mmol) was dissolved in THF (5160 mL) under a nitrogen atmosphere. The reaction mixture was cooled to 0 ° C. and lithium aluminum hydride (1.0 M in THF, 3519 mL, 3519 mmol) was added dropwise. The ice bath was removed and the reaction mixture was stirred at rt for 3 h. The reaction was cooled to 0 ° C. and water (160 mL) was added slowly followed by 15% aqueous NaOH solution (160 mL) and water (500 mL). The mixture was stirred for 10 minutes at room temperature and the reaction was filtered. The remaining solids were washed with hot ethyl acetate (3 x 4.0 L). The combined filtrates were concentrated under reduced pressure to yield a yellow oil. The residue was dissolved in DCM (5160 mL) and the solution cooled to 0 ° C. HCl solution (4.0 M in dioxane, 65 mL) was added dropwise and the mixture was stirred at rt for 15 min. The precipitate was collected by filtration. The solid was washed with ice-cold DCM (100 mL) and dried to give (S)-(1- (aminomethyl) -6-chloro-1,2,3,4-tetrahydronaphthalen-1-yl) methanol hydrochloride Was obtained (192 g, 72.8% yield). ¹ H NMR (400 MHz, Methanol-d ₄ ) δ 7.38-7.36 (d, J = 8.2 Hz, 1H), 7.23-7.20 (m, 2H), 3.81-3.78 (m, 1H), 3.69-3.68 (dd , J = 10.9, 1.3 Hz, 1H), 3.48-3.45 (d, J = 13.1 Hz, 1H), 3.23-3.20 (d, J = 13.2 Hz, 1H), 2.83-2.81 (d, J = 6.3 Hz, 2H), 2.17-2.11 (m, 1H), 1.91-1.85 (m, 2H), 1.83-1.74 (m, 1H); Exchangeable protons were not observed.

Step 3: (S) -Methyl 5-((1- (aminomethyl) -6-chloro-1,2,3,4-tetrahydronaphthalen-1-yl) methoxy) -6-bromopicolinate

To dry (S)-(1- (aminomethyl) -6-chloro-1,2,3,4-tetrahydronaphthalen-1-yl) methanol hydrochloride (150 g, 572 mmol) was dried DMSO (2250 mL). It was dissolved under nitrogen atmosphere at room temperature. Treat the solution with 6-bromo-5-fluoropicolinic acid (151 g, 687 mmol) and treat the resulting solution with potassium 2-methylpropane-2-oleate (218 g, 1945 mmol) at room temperature. It was. The reaction mixture was stirred at room temperature for 2 hours, acetic acid (˜170 mL) was added at room temperature, and then quenched by addition of water (1.5 L) to precipitate a solid. Solids were collected by filtration, washed with water (1.0 L) and dried. Solids were added to a premixed MeOH / H ₂ SO ₄ (10: 1, v / v, 5400 mL) solution and stirred at 80 ° C. for 3 hours. The mixture was cooled to room temperature and the sulfuric acid was quenched by the slow addition of solids K ₂ CO ₃ (600 g). The mixture was suspended in water (2 L) and ethyl acetate (2 L). The layers were separated. The aqueous layer was extracted with ethyl acetate (2 x 2.5 L). The combined organic extracts were washed with brine (2.0 L), dried over Na ₂ S0 ₄ and filtered. The filtrate was concentrated under reduced pressure. Purification by column chromatography on silica gel (60-120 mesh, eluting with MeOH (0% to 5% gradient) in DCM) (S) -methyl 5-((1- (aminomethyl) -6- Chloro-1,2,3,4-tetrahydronaphthalen-1-yl) methoxy) -6-bromopicolinate was obtained as an off-white solid (170 g, 67.6% yield). MS (ESI, cation) m / z 439.0 (M + l). ¹ H NMR (400 MHz, Chloroform-d) δ 8.06-8.04 (dd, J = 8.4, 1.0 Hz, 1H), 7.51-7.49 (d, J = 8.4 Hz, 1H), 7.18-7.14 (m, 3H) , 4.18-4.11 (m, 2H), 3.93 (s, 3H), 3.25-3.17 (m, 2H), 2.80-2.76 (m, 2H), 2.06-1.97 (m, 2H), 1.94-1.85 (tdd, J = 9.5, 6.7, 4.2 Hz, 2H); Exchangeable protons were not observed.

Step 4: methyl 5-(((S) -1-((((((1R, 2R) -2- (acetoxymethyl) cyclobutyl) methyl) amino) methyl) -6-chloro-1,2,3 , 4-tetrahydronaphthalen-1-yl) methoxy) -6-bromopicolinate

(S) -methyl 5-((1- (aminomethyl) -6-chloro-1,2,3,4-tetrahydronaphthalen-1-yl) methoxy) -6-bro in dry DCM (1.7 L) Morphocolinate (170 g, 387 mmol) and acetic acid (1105 mL) were added to a solution of ((1R, 2S) -2-((S)-(1H-benzo [d] [1,2, 3] triazol-1-yl) (hydroxy) methyl) cyclobutyl) methyl acetate (128 g, 464 mmol) was added followed by sodium cyanoborohydride (31.6 g, 503 mmol) at 0 ° C. It was. The reaction was kept at 0 ° C. for 2 hours. The reaction was poured slowly into cold 10% solution of sodium bicarbonate. The aqueous phase was extracted with ethyl acetate (2 x 2.0 L). The combined organic layers were washed with brine (1.0 L), dried over sodium sulphate and concentrated under reduced pressure. Purification by column chromatography on silica gel (60-120 mesh, eluting with MeOH (2% to 5% gradient) in DCM) 5-(((S) -1-((((((1R, 2R ) -2- (acetoxymethyl) cyclobutyl) methyl) amino) methyl) -6-chloro-1,2,3,4-tetrahydronaphthalen-1-yl) methoxy) -6-bromopicolinate Obtained as a yellow liquid (149 g, 66.5% yield). MS (ESI, cation) m / z 579.1 (M + l). ¹ H NMR (400 MHz, Chloroform-d) δ 8.08-8.06 (dt, J = 8.4, 1.3 Hz, 1H), 7.55-7.53 (dd, J = 8.3, 1.6 Hz, 1H), 7.19-7.13 (m, 3H), 4.13 (s, 2H), 4.10-4.00 (t, J = 2.3 Hz, 2H), 3.98 (d, J = 1.4 Hz, 3H), 3.05-2.98 (m, 2H), 2.79-2.78 (m , 2H), 2.69-2.58 (m, 2H), 2.18-2.11 (dd, J = 8.9, 4.9 Hz, 2H), 2.09-2.06 (dq, J = 9.7, 4.8, 3.1 Hz, 1H), 2.00 (t , J = 1.3 Hz, 3H), 1.97-1.82 (m, 6H), 1.65-1.61 (d, J = 9.2 Hz, 1H), 1.59-1.51 (q, J = 8.9 Hz, 1H).

Step 5: (S) -Methyl 5 '-(((1R, 2R) -2- (acetoxymethyl) cyclobutyl) methyl) -6-chloro-3,4,4', 5'-tetrahydro-2H , 2'H-spiro [naphthalene-1,3'-pyrido [3,2-b] [1,4] oxazepine] -7'-carboxylate

Methyl 5-(((S) -1-((((((1R, 2R) -2- (acetoxymethyl) cyclobutyl) methyl) amino) methyl) -6-chloro-1,2,3,4- N-ethyl-N-isopropylpropane- in tetrahydronaphthalen-1-yl) methoxy) -6-bromopicolinate (36 g, 62.1 mmol) and N-methyl-2-pyrrolidone (360 mL) A solution of 2-amine (161 mL, 933 mmol) was stirred for 16 h at 130 ° C. under a nitrogen atmosphere. The reaction was cooled to room temperature and diluted with ethyl acetate (1.0 L). The mixture was washed with water (5 x 400 mL). The organic layer was dried over sulfuric acid, filtered and concentrated under reduced pressure. Purification by column chromatography on silica gel (60-120 mesh, EtOAc in hexanes (0% to 10%)) (S) -methyl5 '-(((1R, 2R) -2- (acetoxymethyl ) Cyclobutyl) methyl) -6-chloro-3,4,4 ', 5'-tetrahydro-2H, 2'H-spiro [naphthalene-1,3'-pyrido [3,2-b] [1 , 4] oxazepine] -7'-carboxylate was obtained as a yellow liquid (16 g, 51.7% yield). MS (ESI, cation) m / z 499.1 (M + l). ¹ H NMR (400 MHz, Chloroform-d) δ 7.72-7.70 (d, J = 8.5 Hz, 1H), 7.46-7.44 (dd, J = 7.9, 1.1 Hz, 1H), 7.21-7.20 (dd, J = 8.5, 2.2 Hz, 1H), 7.18-7.11 (m, 2H), 4.18-4.15 (d, J = 12.2 Hz, 1H), 4.05-3.98 (m, 3H), 3.95-3.93 (d, J = 4.5 Hz , 1H), 3.91-3.89 (d, J = 1.0 Hz, 3H), 3.74-3.70 (d, J = 14.5 Hz, 1H), 3.42-3.32 (m, 2H), 2.79-2.76 (dt, J = 9.0 , 5.1 Hz, 2H), 2.55-2.49 (dt, J = 15.5, 7.4 Hz, 2H), 1.98-1.85 (m, 8H), 1.76-1.74 (t, J = 9.4 Hz, 1H), 1.62-1.61 ( d, J = 1.1 Hz, 1H), 1.50-1.49 (d, J = 1.1 Hz, 1H).

Step 6: (S) -Methyl 6-chloro-5 '-(((1R, 2R) -2- (hydroxymethyl) cyclobutyl) methyl) -3,4,4', 5'-tetrahydro-2H , 2'H-spiro [naphthalene-1,3'-pyrido [3,2-b] [1,4] oxazepine] -7'-carboxylate

(S) -methyl 5 '-(((1R, 2R) -2- (acetoxymethyl) cyclobutyl) methyl) -6-chloro-3,4,4 in THF (680 mL) and water (680 mL) ', 5'-tetrahydro-2H, 2'H-spiro [naphthalene-1,3'-pyrido [3,2-b] [1,4] oxazepine] -7'-carboxylate (68 g, 136 mmol) was added lithium hydroxide monohydrate (22.87 g, 545 mmol) at room temperature. The reaction was stirred at rt for 12 h. The reaction was concentrated under reduced pressure, the residue was dissolved in MTBE (1.0 L) to add 10% hydrous citric acid solution (500 mL) and the solution was stirred for 10 minutes. The layers were separated and the organic layer was washed with brine (500 mL), dried over sodium sulphate and concentrated under reduced pressure. The concentrate was dissolved in dry methanol (600 mL) and cooled to 0 ° C. Thionyl chloride (14.92 mL, 204 mmol) was added and the reaction was heated at 60 ° C. for 12 h. The reaction was cooled to 0 ° C. and quenched by the slow addition of 10% sodium bicarbonate solution (500 mL) and extracted with ethyl acetate (2 × 500 mL). The combined organic layers were washed with brine (300 mL), dried over sodium sulphate and concentrated under reduced pressure. The concentrate was suspended in acetonitrile (140 mL) and water (140 mL) was added. The mixture was stirred for 10 minutes. The solid was collected by filtration and dried to give (S) -methyl 6-chloro-5 '-(((1R, 2R) -2- (hydroxymethyl) cyclobutyl) methyl) -3,4,4', 5'-tetrahydro-2H, 2'H-spiro [naphthalene-1,3'-pyrido [3,2-b] [1,4] oxazepine] -7'-carboxylate was obtained (58 g) , 93% yield). MS (ESI, cation) m / z 457.1 (M + l). ¹ H NMR (400 MHz, Chloroform-d) δ 7.73-7.72 (d, J = 8.5 Hz, 1H), 7.47-7.45 (d, J = 7.9 Hz, 1H), 7.21-7.19 (dd, J = 8.5, 2.3 Hz, 1H), 7.14-7.11 (m, 2H), 4.44-4.40 (m, 1H), 4.16-4.13 (d, J = 12.1 Hz, 1H), 4.06-4.03 (d, J = 12.1 Hz, 1H ), 3.95 (s, 3H), 3.84-3.80 (d, J = 14.4 Hz, 1H), 3.75-3.68 (m, 1H), 3.57-3.56 (ddt, J = 14.1, 9.3, 4.2 Hz, 2H), 3.37-3.36 (d, J = 14.5 Hz, 1H), 2.96-2.90 (dd, J = 14.0, 9.1 Hz, 1H), 2.82-2.76 (m, 2H), 2.58-2.54 (m, 1H), 2.32 ( td, J = 12.2, 10.4, 6.3 Hz, 1H), 2.02-1.95 (m, 3H), 1.88-1.83 (m, 2H), 1.67-1.55 (m, 2H), 1.49-1.43 (m, 1H).

Step 7: (S) -Methyl 6-chloro-5 '-(((1R, 2R) -2-formylcyclobutyl) methyl) -3,4,4', 5'-tetrahydro-2H, 2 ' H-spiro [naphthalene-1,3'-pyrido [3,2-b] [1,4] oxazepine] -7'-carboxylate

A 1 L three-necked flask equipped with a mechanical stir bar and temperature probe was charged with DCM (220 mL, 5V) followed by oxalyl chloride (10.16 mL, 116 mmol). The solution was cooled to −73 ° C. in a dry aid acetone bath. DMSO (17.15 mL, 242 mmol) was added via syringe over 7 minutes (during addition the internal temperature rose from -74 ° C to -60 ° C). The mixture was kept for 14 minutes and (S) -methyl 6-chloro-5 '-(((1R, 2R) -2- (hydroxymethyl) in DCM (220 mL, 5V) cooled in a dry ice acetone bath. Cyclobutyl) methyl) -3,4,4 ', 5'-tetrahydro-2H, 2'H-spiro [naphthalene-1,3'-pyrido [3,2-b] [1,4] oxazepine ] -7'-carboxylate (44.2 g, 97 mmol) solution was added via cannula over 12 minutes (internal temperature rises from -75 ° C to -72 ° C during the addition). The solution was stirred for 17 minutes and triethylamine (67.4 mL, 484 mmol) was added over 7 minutes (during addition the internal temperature rose from -76 ° C to -65 ° C). After addition of Et ₃ N, the reaction was held in a dry ice acetone bath for 5 minutes, then warmed up to 7 ° C. over 4 hours and quenched with water (220 mL, 5v) (internal process temperature 7 Rises from 15 ° C. to 15 ° C.). The mixture was transferred to a separatory funnel and the aqueous layer was discarded. The bottom layer was washed with saturated NH ₄ Cl (220 mL, 5V), 1: 1 ratio of water and saturated NaHCO ₃ (220 mL, 5V), and 1: 1 ratio of water and brine (220 mL, 5V). . The bottom organic layer was dried over MgSO 4, filtered through fine frit and concentrated under reduced pressure to give an off-white foam. The foam was dissolved in 1: 1 ratio of EtOAc / DCM (100 mL) and filtered through a pad of 2 cm of silica (eluted with 100 mL of EtOAc / DCM at 100 mL of 1: 1 ratio). The solution was concentrated under reduced pressure, diluted with PhMe (100 mL) and concentrated. This was repeated two more times and the product (S) -methyl 6-chloro-5 '-(((1R, 2R) -2-formylcyclobutyl) methyl) -3,4,4', 5'-tetra Hydro-2H, 2'H-spiro [naphthalene-1,3'-pyrido [3,2-b] [1,4] oxazepine] -7'-carboxylate was used without further purification. MS (ESI, cation) m / z 454.9 (M + H) ⁺ .

Step 8: (1S) -Methyl 6-chloro-5 '-(((1R, 2R) -2- (hydroxyallyl) cyclobutyl) methyl) -3,4,4', 5'-tetrahydro-2H , 2'H-spiro [naphthalene-1,3'-pyrido [3,2-b] [1,4] oxazepine] -7'-carboxylate

In a 2 L jacketed reactor (-)-cinconidine (5.69 g, 19.34 mmol) was added followed by PhMe (220 mL, 5V) and THF (220 mL, 5V). The solution was cooled to -23 ° C (based on internal temperature) and zinc chloride (1.9 M in 2-methyltetrahydrofuran, 81 mL, 155 mmol) was added over 3 minutes (internal temperature during addition was -23 ° C). To -19 ° C.). The solution was stirred for 5 minutes and vinylmagnesium chloride (1.6 M solution in THF, 206 mL, 329 mmol) was added over 24 minutes via the addition funnel (during the addition the internal temperature rose from -21 ° C to -13 ° C). box). The solution was stirred for 20 minutes (internal temperature dropped to -22 ° C) and (S) -methyl 6-chloro-5'- in PhMe (220 mL, 5V) prepared in the previous step and cooled in an ice bath. (((1R, 2R) -2-formylcyclobutyl) methyl) -3,4,4 ', 5'-tetrahydro-2H, 2'H-spiro [naphthalene-1,3'-pyrido [3 , 2-b] [1,4] oxazepine] -7'-carboxylate solution was added via cannula over 8 minutes (internal temperature rose from -22 ° C to -15 ° C during the addition). The reaction was stirred at -20 ° C for 1 hour and warmed to 0 ° C. After 45 minutes, the reaction was cooled to -8 ° C and quenched with saturated NH ₄ Cl (350 mL, 8V). Water (88 mL, 2V) was added. Ammonium hydroxide (20 mL, 0.45 V) was added and the solids dissolved. The prime minister abandoned. The organic phase is washed with saturated NH ₄ Cl (220 mL, 5V), 1 M citric acid (4 × 88 mL, 2V), 1: 1 ratio of water and brine (440 mL, 10V), dried over MgSO ₄ , Filtration and concentration gave a yellow oil. MeOH (200 mL) was added and removed under reduced pressure. This was repeated two more times and the product (S) -methyl 6-chloro-5 '-(((1R, 2R) -2- (1-hydroxyallyl) cyclobutyl) methyl) -3,4,4' , 5'-tetrahydro-2H, 2'H-spiro [naphthalene-1,3'-pyrido [3,2-b] [1,4] oxazepine] -7'-carboxylate without further purification Used as a mixture of stereoisomers. MS (ESI, cation) m / z 483.0 (M + H) ⁺ .

Step 9: (1S) -6-chloro-5 '-(((1R, 2R) -2- (1-hydroxyallyl) cyclobutyl) methyl) -3,4,4', 5'-tetrahydro- 2H, 2'H-spiro [naphthalene-1,3'-pyrido [3,2-b] [1,4] oxazepine] -7'-carboxylic acid

(1S) -methyl 6-chloro-5 '-(((1R, 2R) -2 in MeOH (234 mL, 5V) and THF (234 mL, 5V) prepared in the previous step in a 2 L jacketed reactor -(Hydroxyallyl) cyclobutyl) methyl) -3,4,4 ', 5'-tetrahydro-2H, 2'H-spiro [naphthalene-1,3'-pyrido [3,2-b] [ 1,4] oxazepine] -7'-carboxylate solution was added. Lithium hydroxide monohydrate (16.23 g, 387 mmol) was added and the reaction stirred at rt for 17 h. Citric acid (1 M in water, 180 mL) was added followed by water (187 mL, 4V) and EtOAc (234 mL, 5V). All solids were dissolved. The mixture was removed from the reactor and placed in a 3 L flask, and the mixture was concentrated to half its original volume. EtOAc (234 mL, 5V) was added and the mixture was transferred to a separatory funnel. The pH of the aqueous layer was 5. The water column was discarded. The organic layer was washed with 1: 1 ratio of water and brine (235 mL, 5V), dried over MgSO 4 and concentrated to give 47.0 g of yellow solid, which was 79 wt% of (1S) -6-chloro-5 '-(((1R, 2R) -2- (1-hydroxyallyl) cyclobutyl) methyl) -3,4,4', 5'-tetrahydro-2H, 2'H-spiro [naphthalene-1, It was a diastereomeric mixture with 3'-pyrido [3,2-b] [1,4] oxazepine] -7'-carboxylic acid (37.1 g, 79 mmol, 82% yield). MS (ESI, cation) m / z 469.0 (M + H) ⁺ .

Step 10: (1S) -6-Chloro-5 '-(((1R, 2R) -2- (1-hydroxyallyl) cyclobutyl) methyl) -N-(((2R, 3S) -3-methyl Hex-5-en-2-yl) sulfonyl) -3,4,4 ', 5'-tetrahydro-2H, 2'H-spiro [naphthalene-1,3'-pyrido [3,2-b ] [1,4] oxazepine] -7'-carboxamide

(1S) -6-chloro-5 '-(((1R, 2R) -2- (1-hydroxyallyl) cyclobutyl) methyl) -3,4,4', 5 in 500 mL 1-neck flask '-Tetrahydro-2H, 2'H-spiro [naphthalene-1,3'-pyrido [3,2-b] [1,4] oxazepine] -7'-carboxylic acid (34.7 g, 58.5 mmol), PhMe (100 mL) to a mixture of 4- (dimethylamino) pyridine (21.42 g, 175 mmol), and (2R, 3S) -3-methylhex-5-ene-2-sulfonamide (21.41 g, 117 mmol). ) Was added. PhMe was removed under reduced pressure, and the concentrate was diluted with DCM (347 mL, 10V) and transferred into a 1 L three-necked flask equipped with a temperature probe and magnetic stirrer. Triethylamine (24.44 mL, 175 mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide HCl (22.41 g, 117 mmol) were added and the reaction stirred at room temperature. After 43 hours, the reaction was diluted with water (240 mL, 7V) and transferred to a separatory funnel. The pH of the aqueous phase was adjusted to 4 using 1 M citric acid (240 mL, 7V) and the aqueous phase was discarded. The organic phase was washed with 1: 1 ratio of brine and water (240 mL, 7V), dried over MgSO ₄ , filtered and concentrated. Purification by flash chromatography using silica gel (330 g silica; eluting with 50% to 100% DCM in heptane) gave (1S) -6-chloro-5 '-(((1R, 2R) -2- (1-hydroxyallyl) cyclobutyl) methyl) -N-(((2R, 3S) -3-methylhex-5-en-2-yl) sulfonyl) -3,4,4 ', 5'- Tetrahydro-2H, 2'H-spiro [naphthalene-1,3'-pyrido [3,2-b] [1,4] oxazepine] -7'-carboxamide was obtained as pale yellow foam ( 24.7 g, 39.3 mmol, 67% yield). A diastereomeric mixture was obtained. MS (ESI, cation) m / z 628.0 (M + H) ⁺ .

Step 11: (S) -5 '-(((1R, 2R) -2-acryloylcyclobutyl) methyl) -6-chloro-N-(((2R, 3S) -3-methylhex-5- En-2-yl) sulfonyl) -3,4,4 ', 5'-tetrahydro-2H, 2'H-spiro [naphthalene-1,3'-pyrido [3,2-b] [1, 4] oxazepine] -7'-carboxamide

(1S) -6-chloro-5 '-(((1R, 2R) -2- (1-hydr) in DCM (28 mL, 10V) in a 100 mL one-necked flask with temperature probe and magnetic stir bar Roxyallyl) cyclobutyl) methyl) -N-(((2R, 3S) -3-methylhex-5-en-2-yl) sulfonyl) -3,4,4 ', 5'-tetrahydro-2H A solution of 2, H-spiro [naphthalene-1,3'-pyrido [3,2-b] [1,4] oxazepine] -7'-carboxamide (2.82 g, 4.49 mmol) in an ice bath Cool to 2 ° C. and des-martin periodinan (2.094 g, 4.94 mmol) was added in one portion. The reaction was allowed to warm to room temperature over 20 minutes and stirred at room temperature for 30 minutes. The solution was cooled to 2 ° C. in an ice bath, quenched with a solution of sodium thiosulfate (2.4 g) in water (8.4 mL, 3 V), followed by saturated NaOCO ₃ (20 mL, 7 V). During quenching, the internal temperature was raised from 2 ° C to 7 ° C. The reaction was removed from the ice bath and warmed to room temperature and stirred for 30 minutes. The mixture was transferred to a separatory funnel. The pH was adjusted to 7 with 1 M citric acid. The water column was discarded. The organic phase was washed with 1: 1 ratio of brine and water (28 mL, 10V), dried over MgSO ₄ , filtered and concentrated to give a yellow foam. The concentrate was dissolved in 10% EtOAc in DCM (˜50 mL) and filtered through a pad of 1 cm silica gel (eluted with 10% EtOAc in 100 mL of DCM). The filtrate was concentrated to give (S) -5 '-(((1R, 2R) -2-acryloylcyclobutyl) methyl) -6-chloro-N-(((2R, 3S) -3-methylhex-5 -En-2-yl) sulfonyl) -3,4,4 ', 5'-tetrahydro-2H, 2'H-spiro [naphthalene-1,3'-pyrido [3,2-b] [1 , 4] oxazepine] -7'-carboxamide as a light yellow foam and used without these further purification. MS (ESI, cation) m / z 625.8 (M + H) ⁺ . ¹ H NMR (400 MHz, Chloroform-d) δ ppm 1.14 (d, J = 6.85 Hz, 3H), 1.45 (d, J = 7.04 Hz, 3H), 1.48-1.56 (m, 1H), 1.81-2.05 ( m, 6H), 2.10-2.19 (m, 2H), 2.27 (q, J = 8.80 Hz, 1H), 2.62 (qd, J = 7.14, 2.45 Hz, 1H), 2.73-2.87 (m, 2H), 3.04 -3.17 (m, 1H), 3.30 (q, J = 8.80 Hz, 1H), 3.36-3.43 (m, 1H), 3.43-3.47 (m, 1H), 3.78 (d, J = 14.48 Hz, 1H), 3.89-4.07 (m, 3H), 4.20 (d, J = 12.32 Hz, 1H), 5.07-5.15 (m, 2H), 5.74-5.87 (m, 2H), 6.15-6.32 (m, 2H), 7.12 ( d, J = 2.15 Hz, 1H), 7.18-7.22 (m, 2H), 7.58 (d, J = 7.83 Hz, 1H), 7.69 (d, J = 8.41 Hz, 1H), 9.90 (s, 1H).

Step 12: (1S, 3'R, 6'R, 8'E, 11'S, 12'R) -6-Chloro-11 ', 12'-dimethyl-3,4-dihydro-2H, 7'H , 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14,25] triazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] Pentacosa [8,16,18,24] tetraene] -7 ', 15'-dione 13', 13'-dioxide

PhMe (1.8 L, 250 V) was charged to a four-necked flask equipped with a magnetic stir bar, temperature probe, and an air cooled condenser. The solvent was heated to 80 ° C. and the gas dispersion tube was immersed in the solvent. Through a gas dispersion tube, nitrogen gas bubbles were passed through the solvent. (S) -5 '-(((1R, 2R) -2-acryloylcyclobutyl) methyl) -6-chloro-N-((((2R, 3S) -3-methylhex in PhMe (65 mL) -5-en-2-yl) sulfonyl) -3,4,4 ', 5'-tetrahydro-2H, 2'H-spiro [naphthalene-1,3'-pyrido [3,2-b] A solution of [1,4] oxazepine] -7'-carboxamide (8.93 g, 80 wt%, 11.41 mmol) was added over 2 hours via an addition funnel. During the addition of the diene, Umicore M73 SIMes (Umicore AG & Co. KG, Precious Metals Chemistry, Rodenbacher Chaussee 4, 63457 Hanau-Wolfgang, Germany) were subjected to the same 4 times via syringe as PhMe (4 mL) suspension. Divided by t = 0 minutes, t = 30 minutes, t = 60 minutes, and t = 90 minutes (total amount of catalyst was 0.346 g, 0.456 mmol). After the addition of the diene was complete, the reaction was further stirred at 80 ° C. for 1 hour. The reaction was cooled to room temperature, 2- (2- (vinyloxy) ethoxy) ethanol (0.125 mL, 0.913 mmol) and SilaMetS thiol (SiliCycle Inc. 2500, Parc-Technologique Blvd, Quebec, Canada) 7.71 g) was added. The mixture was stirred at rt for 18 h and the SilaMetS thiol was removed by filtration, washed with EtOAc and concentrated to give a tan solid. MeOH (˜50 mL) was added and removed under reduced pressure. MeOH (107 mL, 15 V) was added and the slurry was stirred for 3 days at room temperature and collected by filtration. The solid was washed with MeOH (1 x 40 mL), nitrogen was flowed forward and dried on frit under vacuum to yield 6.39 g of an off-white solid, which was 66 wt% of (1S, 3'R, 6'R, 8'E, 11'S, 12'R) -6-Chloro-11 ', 12'-dimethyl-3,4-dihydro-2H, 7'H, 15'H-spiro [naphthalene-1,22'- [20] oxa [13] thia [1,14,25] triazatetracyclo [14.7.2.0-3,6-0.0 ~ 19,24] pentacosa [8,16,18,24] tetraene -7 ', 15'-dione 13', 13'-dioxide (4.22 g, 7.0 mmol, 62% yield). MS (ESI, cation) m / z 598.1 (M + H) ⁺ .

Step 13: (1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7 '-(hydroxymethyl) -7'-methoxy-11', 12 '-Dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-[20] oxa [13] thia [1,14,25] triazatetracyclo [14.7.2.0 ~ 3,6 ~ .0 ~ 19,24 ~] Pentacosa [8,16,18,24] tetraene] -15'-on 13 ', 13'-dioxide

(1S, 3'R, 6'R, 8'E, 11'S, 12'R) -6-chloro-11 ', 12'- in a three-necked flask equipped with a temperature probe, septum, and nitrogen inlet. Dimethyl-3,4-dihydro-2H, 7'H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14,25] triazatetracyclo [14.7 .2.0 ~ 3,6 ~ .0 ~ 19,24 ~] Pentacosa [8,16,18,24] tetraene] -7 ', 15'-dione 13', 13'-dioxide (6.33 g, 66 wt%, 6.98 mmol) and trimethylsulfonium iodide (2.138 g, 10.48 mmol) were charged. DMSO (35 mL) and THF (8.75 mL) were added and the mixture was stirred at room temperature for 20 minutes until the solids dissolved. The solution was cooled in an ice bath. When the internal temperature reached 6.5 ° C., potassium tert-butoxide (1.0 M solution in THF, 17.46 mL, 17.46 mmol) was slowly added via syringe. After 40 minutes, a small amount of trimethylsulfonium iodide was added followed by potassium tert-butoxide (1 M solution in THF, 1.2 mL, 1.2 mmol). After 15 minutes, zinc (II) trifluoromethanesulfonate (0.5 M in MeOH, 84 mL, 41.9 mmol) was added over 5 minutes. After addition, the reaction was allowed to warm to room temperature, stirred for 2 hours, and quenched with saturated ammonium chloride (˜150 mL). Water and EtOAc were added. The aqueous phase was extracted three times with EtOAc. The combined organic extracts were concentrated. The concentrate was dissolved in EtOAc, washed with water (2 ×) and brine (1 ×), dried over Na ₂ SO ₄ , filtered and concentrated. The material was absorbed onto silica gel. Purification by flash column chromatography (330 g of silica, eluting with 10% to 80% EtOAc in heptane (containing 2% AcOH)) gave 5.17 g of a pale yellow solid, which was 57 wt% ( 1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7 '-(hydroxymethyl) -7'-methoxy-11', 12'-dimethyl -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14,25] triazatetracyclo [14.7.2.0-3,6 .0-19,24-] pentacosa [8,16,18,24] tetraene] -15'-one 13 ', 13'-dioxide (2.93 mg, 4.55 mmol, 65% yield). MS (ESI, cation) m / z 644.0 (M + H) ⁺ .

Step 14: (1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-Chloro-7'-methoxy-11 ', 12'-dimethyl-15'-oxo -3,4-dihydro-2H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14,25] triazatetracyclo [14.7.2.0-3,6-0.0 ... 19,24 ~] pentacosa [8,16,18,24] tetraene] -7'-carbaldehyde 13 ', 13'-dioxide

(1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7 '-(hydroxymethyl) -7 in DCM (60 mL) and DMSO (30 mL) '-Methoxy-11', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14,25 ] Triazatetracyclo [14.7.2.0-3,6-0.0-19,24-] pentacosa [8,16,18,24] tetraene] -15'-one 13 ', 13'-dioxide (79 wt%, 7.4 g, 9.07 mmol) was added N, N-diisopropylethylamine (7.92 mL, 45.4 mmol). The solution was cooled in an ice bath and pyridine-sulfur trioxide complex (3.61 g, 22.69 mmol) was added. After 40 minutes, the reaction was quenched with saturated ammonium chloride and diluted with water and EtOAc. The organic phase was washed with water. The combined aqueous phases were extracted twice with EtOAc. The combined organic phases were washed with 50% saturated ammonium chloride (2 x), brine, dried over Na ₂ S0 ₄ , filtered and concentrated (1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-methoxy-11 ', 12'-dimethyl-15'-oxo-3,4-dihydro-2H-spiro [naphthalene-1,22'-[20] Oxa [13] thia [1,14,25] triazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraen] -7 ' -Carbaldehyde 13 ', 13'-dioxide was obtained, which was used without further purification. MS (ESI, cation) m / z 641.9 (M + H) ⁺ .

Step 15: (1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-Chloro-7 '-((9aS) -hexahydropyrazino [2,1-c] [1,4] oxazine-8 (1H) -ylmethyl) -7'-methoxy-11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1 , 22 '-[20] oxa [13] thia [1,14,25] triazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24 ] Tetraene] -15'-on 13 ', 13'-dioxide

(1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-methoxy-11 ', 12'-dimethyl in DCM (82 mL) at room temperature -15'-oxo-3,4-dihydro-2H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [-1 1,14,25] triazatetracyclo [14.7.2.0- 3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraene] -7'-carbaldehyde 13 ', 13'-dioxide (5.28 g, 8.22 mmol) and (S) To a solution of octahydropyrazino [2,1-c] [1,4] oxazine (3.51 g, 24.67 mmol) was added acetic acid (0.475 mL, 8.22 mmol). The mixture was stirred at rt for 1 h and sodium triacetoxyborohydride (2.091 g, 9.87 mmol) was added slowly over 1 min. After 1 h, additional sodium triacetoxyborohydride (300 mg) was added. The reaction was stirred for 30 minutes and quenched with saturated NH ₄ Cl. The aqueous phase was extracted three times with DCM. The combined organic extracts were washed with saturated NH ₄ Cl (1 ×) and brine (1 ×), dried over Na ₂ SO ₄ , filtered and concentrated. Purification by flash chromatography (330 g of silica; eluted with 0% to 10% MeOH in DCM) (1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6 -Chloro-7 '-((9aS) -hexahydropyrazino [2,1-c] [1,4] oxazin-8 (1H) -ylmethyl) -7'-methoxy-11', 12 ' -Dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14,25] triazatetracyclo [14.7.2.0- 3,6 ~ .0 ~ 19,24 ~] Pentacosa [8,16,18,24] tetraene] -15'-one 13 ', 13'-dioxide was obtained as an off-white solid (6.02 g, 7.83 mmol). , 95% yield). MS (ESI, cation) m / z 768.2 (M + H) ⁺ . ¹ H NMR (400 MHz, Chloroform-d) δ ppm 1.17 (d, J = 6.85 Hz, 3H), 1.46 (d, J = 7.04 Hz, 3H), 1.48-1.63 (m, 4H), 1.68-2.09 ( m, 8H), 2.19 (br d, J = 17.22 Hz, 1H), 2.49 (br s, 3H), 2.33 (br s, 3H), 2.42 (br s, 1H), 2.55-2.70 (m, 2H) , 2.77-3.04 (m, 6H), 3.08 (s, 3H), 3.15 (br s, 1H), 3.54 (br s, 1H), 3.66 (br s, 1H), 3.74-3.96 (m, 2H), 3.95-3.95 (m, 1H), 4.02 (d, J = 12.32 Hz, 1H), 4.09-4.21 (m, 2H), 5.51 (br d, J = 17.02 Hz, 1H), 5.64 (br d, J = 16.82 Hz, 1H), 7.11-7.17 (m, 2H), 7.21 (dd, J = 8.51, 2.25 Hz, 1H), 7.38 (d, J = 7.82 Hz, 1H), 7.67 (d, J = 8.61 Hz, 1 H), 9.12 (br s, 1 H).

Example 19

(1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-methoxy-11 ', 12'-dimethyl-7'-((4- (3-oxetanyl) -1-piperazinyl) methyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1, 14,25] triazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraene] -15'-one 13 ', 13'- Dioxide

General method 13

(1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-methoxy-11 ', 12'-dimethyl in DCM (374 μL) at room temperature -15'-oxo-3,4-dihydro-2H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [-1 1,14,25] triazatetracyclo [14.7.2.0- 3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraene] -7'-carbaldehyde 13 ', 13'-dioxide (12 mg, 0.019 mmol) and 1- ( To a solution of oxetan-3-yl) piperazine (26.6 mg, 0.187 mmol) were added a few drops of titanium (IV) isopropoxide. The mixture was stirred at rt for 8 h and sodium triacetoxyborohydride (15.84 mg, 0.075 mmol) was added slowly over 1 min. The reaction was stirred overnight and quenched with 5 mL of 1 N HCl solution. The aqueous phase was extracted three times with DCM. The combined organic extracts were concentrated. Purify the residue by prep-HPLC (1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-methoxy-11 ', 12'- Dimethyl-7 '-((4- (3-oxetanyl) -1-piperazinyl) methyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-[ 20] oxa [13] thia [1,14,25] triazatetracyclo [14.7.2.0-3,6-0.0-19,24-] pentacosa [8,16,18,24] tetraene]- 15'-one 13 ', 13'-dioxide was obtained as a TFA salt. MS (ESI, cation) m / z 768.2 (M + H) ⁺ . ¹ H NMR (400 MHz, MeOH-d ₄ ) δ ppm 1.11 (d, J = 6.65 Hz, 3H), 1.39 (d, J = 7.24 Hz, 3H), 1.44-1.58 (m, 1H,) 1.64-2.01 (m, 6 H), 2.03-2.27 (m, 2 H), 2.29-2.43 (m, 2 H,) 2.45-2.56 (m, 1 H), 2.32-3.04 (m, 7 H), 3.35-3.67 (m, 6 H), 3.35-3.65 (m, 6 H), 3.72-3.93 (m, 4 H), 4.03-4.10 (m, 1 H), 4.12-4.28 (m, 2 H), 4.61 (t, J = 6.16 Hz, 2H), 4.69-4.77 (m, 2H), 5.78-5.90 (m, 2H), 7.12 (d, J = 1.96 Hz, 1H), 7.15-7.20 ( m, 1H), 7.21-7.26 (m, 2H), 7.70 (d, J = 8.41 Hz, 1H).

Example 20

(1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7 '-((9aS) -hexahydropyrazino [2,1-c] [1, 4] oxazine-8 (1H) -ylmethyl) -7'-methoxy-12 '-(2-methoxyethyl) -11'-methyl-3,4-dihydro-2H, 15'H-spiro [Naphthalene-1,22 '-[20] oxa [13] thia [1,14,25] triazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16 , 18,24] tetraene] -15'-on 13 ', 13'-dioxide

Step 1: (1S) -6-chloro-5 '-(((1R, 2R) -2- (1-hydroxyallyl) cyclobutyl) methyl) -N-(((3R, 4S) -1-meth Methoxy-4-methylhept-6-en-3-yl) sulfonyl) -3,4,4 ', 5'-tetrahydro-2H, 2'H-spiro [naphthalene-1,3'-pyrido [ 3,2-b] [1,4] oxazepine] -7'-carboxamide

To a solution of (3R, 4S) -1-methoxy-4-methylhept-6-ene-3-sulfonamide (4.94 g, 22.34 mmol) in DCM (80 mL) (1S) -6-chloro-5 ' -(((1R, 2R) -2- (1-hydroxyallyl) cyclobutyl) methyl) -3,4,4 ', 5'-tetrahydro-2H, 2'H-spiro [naphthalene-1,3 '-Pyrido [3,2-b] [1,4] oxazepine] -7'-carboxylic acid (6.8 g, 11.5 mmol), 4- (dimethylamino) pyridine (4.20 g, 34.4 mmol), triethyl Amine (3.2 mL, 23.0 mmol), and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide HCl (6.6 g, 34.4 mmol) were added. The resulting mixture was stirred for 20 hours at room temperature under a nitrogen atmosphere. The reaction was quenched with 2 N HCl (5 mL) and diluted with water (30 mL). The aqueous layer was extracted with DCM (2 x 40 mL). The combined organic layers were dried over MgSO ₄ , filtered and concentrated. The crude product was purified by column chromatography (330 g of silica; 0% to 40% acetone in heptane) to give (1S) -6-chloro-5 '-(((1R, 2R) -2- (1- Hydroxyallyl) cyclobutyl) methyl) -N-(((3R, 4S) -1-methoxy-4-methylhept-6-en-3-yl) sulfonyl) -3,4,4 ', 5 '-Tetrahydro-2H, 2'H-spiro [naphthalene-1,3'-pyrido [3,2-b] [1,4] oxazepine] -7'-carboxamide was obtained as a light brown solid. (6.1 g). ¹ H NMR (dichloromethane-d2) δ 10.43 (br. S., 1H), 7.70 (d, J = 8.4 Hz, 1H), 7.52 (d, J = 7.8 Hz, 1H), 7.19 (d, J = 7.8 Hz, 2H), 7.10 (s, 1H), 5.67-5.87 (m, 2H), 5.19 (d, J = 17.2 Hz, 1H), 5.01-5.12 (m, 3H), 4.60 (d, J = 13.7 Hz, 1H), 4.10-4.20 (m, 1H), 3.96-4.07 (m, 3H), 3.89 (d, J = 14.7 Hz, 1H), 3.53 (t, J = 6.4 Hz, 1H), 3.43- 3.50 (m, 1H), 3.34-3.42 (m, 1H), 3.19-3.25 (m, 2H), 3.13 (s, 1H), 2.82-2.92 (m, 1H), 2.73-2.82 (m, 2H), 2.55-2.69 (m, 1H), 2.37-2.48 (m, 1H), 2.33 (br. S., 1H), 2.04-2.22 (m, 3H), 1.91-2.01 (m, 4H), 1.76-1.91 ( m, 2H), 1.62-1.74 (m, 1H), 1.54-1.61 (m, 1H), 1.41 (t, J = 12.8 Hz, 1H), 1.07 (dd, J = 11.2, 7.0 Hz, 3H). MS (ESI, cation) m / z 672.4 (M + H) ⁺ .

Step 2: (S) -5 '-(((1R, 2R) -2-acryloylcyclobutyl) methyl) -6-chloro-N-(((3R, 4S) -1-methoxy-4- Methylhept-6-en-3-yl) sulfonyl) -3,4,4 ', 5'-tetrahydro-2H, 2'H-spiro [naphthalene-1,3'-pyrido [3,2- b] [1,4] oxazepine] -7'-carboxamide

(1S) -6-chloro-5 '-(((1R, 2R) -2- (1-hydroxyallyl) cyclobutyl) methyl) -N-(((3R, 4S) -1-methoxy-4-methylhept-6-en-3-yl) sulfonyl) -3,4,4 ', 5'-tetrahydro-2H, 2'H-spiro [naphthalene-1, To a solution of 3'-pyrido [3,2-b] [1,4] oxazepine] -7'-carboxamide (6.1 g, 9.07 mmol), des-martin periodinan (4.5 g, 10.61 mmol) was added. Added. After addition, the ice bath was removed and the resulting mixture was warmed to room temperature and stirred for 20 hours. The reaction was quenched with 10% sodium thiosulfate (5 mL) and stirred for 30 minutes. The resulting mixture was washed with saturated NaHCO ₃ (30 mL). The aqueous layer was extracted with DCM (2 x 50 mL). The combined organic layers were dried over MgSO ₄ , filtered and concentrated. The crude product was purified by column chromatography (330 g of silica; 0% to 40% acetone in heptane) to give (S) -5 '-(((1R, 2R) -2-acryloylcyclobutyl) methyl ) -6-chloro-N-(((3R, 4S) -1-methoxy-4-methylhept-6-en-3-yl) sulfonyl) -3,4,4 ', 5'-tetrahydro -2H, 2'H-spiro [naphthalene-1,3'-pyrido [3,2-b] [1,4] oxazepine] -7'-carboxamide was obtained as a light brown foam. ¹ H NMR (dichloromethane-d2) δ 9.25-9.54 (m, 1H), 7.70-7.76 (m, 1H), 7.44-7.51 (m, 1H), 7.14-7.21 (m, 1H), 7.03-7.13 (m, 2H), 5.85-6.03 (m, 2H), 4.13-4.22 (m, 1H), 4.01-4.12 (m, 2H), 3.85-3.99 (m, 1H), 3.72-3.81 (m, 1H) , 3.58-3.70 (m, 2H), 3.29-3.33 (m, 7H), 3.17-3.27 (m, 6H), 2.94-3.04 (m, 3H), 2.83-2.93 (m, 4H), 2.73-2.80 ( m, 2H), 2.51-2.64 (m, 1H), 2.32-2.41 (m, 1H), 2.23-2.31 (m, 1H), 2.05-2.12 (m, 2H), 1.97-2.05 (m, 1H), 1.87-1.96 (m, 2H), 1.76-1.87 (m, 2H), 1.61-1.70 (m, 2H), 1.51-1.59 (m, 5H), 1.40-1.51 (m, 2H), 1.04-1.11 (m , 5H), 0.96-1.02 (m, 3H). MS (ESI, cation) m / z 670.2 (M + H) ⁺ .

Step 3: (1S, 3'R, 6'R, 8'E, 11'S, 12'R) -6-chloro-12 '-(2-methoxyethyl) -11'-methyl-3,4-di Hydro-2H, 7'H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14,25] triazatetracyclo [14.7.2.0-3,6]. 0-19,24-] pentacosa [8,16,18,24] tetraene] -7 ', 15'-dione 13', 13'-dioxide

(S) -5 '-(((1R, 2R) -2-acryloylcyclobutyl) methyl) -6-chloro-N-(((3R in 1,2-dichloromethane (1200 mL) under nitrogen) , 4S) -1-methoxy-4-methylhept-6-en-3-yl) sulfonyl) -3,4,4 ', 5'-tetrahydro-2H, 2'H-spiro [naphthalene-1 2nd generation Hoveyda-Grubbs in a solution of, 3'-pyrido [3,2-b] [1,4] oxazepine] -7'-carboxamide (2.2 g, 3.28 mmol) Catalyst (0.206 g, 0.328 mmol) was added. The resulting mixture was heated at 55 ° C. for 20 hours. The reaction was concentrated to cool to room temperature. The crude product was purified by column chromatography (220 g of silica; 0% to 30% acetone in heptane) (1S, 3'R, 6'R, 8'E, 11'S, 12'R) -6-chloro -12 '-(2-methoxyethyl) -11'-methyl-3,4-dihydro-2H, 7'H, 15'H-spiro [naphthalene-1,22'-[20] oxa [13] Thia [1,14,25] triazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraene] -7 ', 15'- Dione 13 ', 13'-dioxide was obtained as a light yellow solid (1.5 g). ¹ H NMR (dichloromethane-d2) δ 8.69 (s, 1H), 7.72 (d, J = 8.4 Hz, 1H), 7.20 (d, J = 8.4 Hz, 1H), 7.08-7.18 (m, 3H) , 6.71-6.82 (m, 1H), 5.86-5.96 (m, 1H), 4.44 (dd, J = 14.1, 8.4 Hz, 1H), 4.14 (d, J = 12.1 Hz, 1H), 3.99 (d, J = 12.1 Hz, 1H), 3.92 (d, J = 15.3 Hz, 1H), 3.85-3.89 (m, 1H), 3.73-3.82 (m, 1H), 3.70 (dd, J = 8.0, 5.1 Hz, 1H) , 3.59-3.66 (m, 1H), 3.42 (s, 3H), 3.39 (d, J = 14.7 Hz, 1H), 2.94 (dd, J = 14.0, 3.8 Hz, 1H), 2.82-2.90 (m, 1H ), 2.72-2.82 (m, 2H), 2.35-2.45 (m, 1H), 2.26-2.34 (m, 1H), 2.09-2.19 (m, 3H), 1.97-2.06 (m, 2H), 1.75-1.94 (m, 5H), 1.37-1.48 (m, 1H), 1.18 (d, J = 6.8 Hz, 3H). MS (ESI, cation) m / z 642.2 (M + H) ⁺ .

Step 4: (1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7 '-(1,3-dithiane-2-yl) -7'- Hydroxy-12 '-(2-methoxyethyl) -11'-methyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-[20] oxa [13] thia [ 1,14,25] triazatetracyclo [14.7.2.0-3,6-0.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ', 13 '-Dioxide

To a 50 mL oven dry three neck flask equipped with a stir bar and temperature probe was added 1,3-dithiane (0.890 g, 7.40 mmol) and THF (15 mL). The resulting mixture was cooled between -20 ° C and -30 ° C and n-butyllithium solution (2.5 M in hexanes, 2.7 mL, 6.75 mmol) was added dropwise via syringe. The resulting mixture was stirred at −20 ° C. for 30 minutes, cooled down to −70 ° C. and stirred for 20 minutes. To this reaction was added a lanthanum (III) -lithium chloride complex (0.6 M in THF, 1.6 mL, 3.36 mmol, Strem Chemical, Newburyport, MI) dropwise via syringe (internal temperature kept below -70 ° C). ). After 10 minutes, (1S, 3'R, 6'R, 8'E, 11'S, 12'R) -6-chloro-12 '-(2-methoxyethyl) -11'- in THF (5 mL). Methyl-3,4-dihydro-2H, 7'H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14,25] triazatetracyclo [14.7. 2.0 ~ 3,6 ~ .0 ~ 19,24 ~] Pentacosa [8,16,18,24] tetraene] -7 ', 15'-dione 13', 13'-dioxide (0.430 g, 0.670 mmol ) Was added dropwise (internal temperature was kept below -70 ℃). After addition, the reaction was stirred at -70 ° C for 15 minutes. The reaction was quenched with saturated NH ₄ Cl (3 mL), warmed to room temperature and partitioned between EtOAc (60 mL) and water (30 mL). The organic layer was dried over MgSO ₄ , filtered and concentrated. Purified by column chromatography (80 g of silica; 0% to 30% acetone in heptane) to (1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro -7 '-(1,3-dithiane-2-yl) -7'-hydroxy-12'-(2-methoxyethyl) -11'-methyl-3,4-dihydro-2H, 15 ' H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14,25] triazatetracyclo [14.7.2.0-3,6-0.0-19,24-] pentacosa [ 8,16,18,24] tetraen] -15'-one 13 ', 13'-dioxide was obtained as a white solid (0.350 g). ¹ H NMR (dichloroheptane-d 2) δ 9.24 (br. S., 1H), 7.65-7.73 (m, 1H), 7.35-7.41 (m, 1H), 7.19 (d, J = 7.8 Hz, 2H) , 7.11 (s, 1H), 5.76-5.87 (m, 1H), 5.60-5.71 (m, 1H), 4.61 (dd, J = 13.5, 4.9 Hz, 1H), 4.12-4.22 (m, 2H), 3.94 -4.03 (m, 2H), 3.89 (d, J = 14.5 Hz, 1H), 3.53-3.63 (m, 2H), 3.44 (d, J = 14.5 Hz, 1H), 3.32 (s, 3H), 2.94- 3.04 (m, 2H), 2.85-2.93 (m, 4H), 2.73-2.84 (m, 3H), 2.54-2.70 (m, 2H), 2.17-2.33 (m, 2H), 2.04-2.13 (m, 4H ), 1.87-2.00 (m, 3H), 1.71-1.83 (m, 3H), 1.64 (dt, J = 18.6, 9.5 Hz, 1H), 1.47 (d, J = 14.9 Hz, 1H), 1.15 (d, J = 6.8 Hz, 3H). MS (ESI, cation) m / z 762.2 (M + H) ⁺ .

Step 5: (1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-Chloro-7 '-(1,3-dithiane-2-yl) -7'- Methoxy-12 '-(2-methoxyethyl) -11'-methyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-[20] oxa [13] thia [ 1,14,25] triazatetracyclo [14.7.2.0-3,6-0.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ', 13 '-Dioxide

In a 15 mL flask, (1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7 '-(1,3-dithiane-2-yl) -7'-hydroxy-12 '-(2-methoxyethyl) -11'-methyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-[20] oxa [ 13] thia [1,14,25] triazatetracyclo [14.7.2.0-3,6 ~ .0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ', 13'-dioxide (0.350 g, 0.459 mmol) and THF (15.0 mL) were added. The mixture was cooled to 0 ° C. and sodium hydride (60 wt% in oil, 0.165 g, 4.13 mmol) was added. After addition the ice bath was removed and the mixture was stirred at room temperature for 20 minutes before iodine methane (0.520 mL, 8.37 mmol) was added. The mixture was stirred at rt for 2 h and then quenched with water (5 mL). The resulting mixture was partitioned between EtOAc (50 mL) and water (20 mL). The organic layer was dried over MgSO ₄ , filtered and concentrated. Purified by column chromatography (40 g of silica; 0% to 30% acetone in heptane) to (1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro -7 '-(1,3-dithiane-2-yl) -7'-methoxy-12'-(2-methoxyethyl) -11'-methyl-3,4-dihydro-2H, 15 ' H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14,25] triazatetracyclo [14.7.2.0-3,6-0.0-19,24-] pentacosa [ 8,16,18,24] tetraen] -15'-one 13 ', 13'-dioxide was obtained as a white solid. ¹ H NMR (dichloromethane-d2) δ 9.20 (br. S., 1H), 7.69 (d, J = 8.4 Hz, 1H), 7.36 (d, J = 7.8 Hz, 1H), 7.16-7.22 (m , 2H), 7.11 (s, 1H), 5.73-5.86 (m, 1H), 5.49-5.60 (m, 1H), 4.82 (dd, J = 14.0, 5.0 Hz, 1H), 4.37 (s, 1H), 4.09-4.20 (m, 2H), 3.99 (d, J = 12.3 Hz, 1H), 3.91 (d, J = 14.5 Hz, 1H), 3.56-3.71 (m, 2H), 3.40-3.50 (m, 1H) , 3.33 (s, 3H), 3.22 (s, 3H), 3.09 (br. S., 1H), 2.92-3.00 (m, 1H), 2.83-2.91 (m, 4H), 2.75-2.83 (m, 2H ), 2.66-2.74 (m, 1H), 2.63 (br. S., 1H), 2.17-2.33 (m, 2H), 2.04-2.14 (m, 3H), 1.91 (td, J = 11.7, 3.6 Hz, 4H), 1.71-1.80 (m, 1H), 1.62-1.70 (m, 2H), 1.54-1.62 (m, 1H), 1.39-1.49 (m, 1H), 1.15 (d, J = 6.8 Hz, 3H) . MS (ESI, cation) m / z 776.2 (M + H) ⁺ .

Step 6: (1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-methoxy-12 '-(2-methoxyethyl) -11' -Methyl-15'-oxo-3,4-dihydro-2H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14,25] triazatetracyclo [14.7.2.0- 3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraene] -7'-carbaldehyde 13 ', 13'-dioxide

(1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7 '-(1,3-ditian-2-yl) in acetonitrile (12.0 mL) -7'-methoxy-12 '-(2-methoxyethyl) -11'-methyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-[20] oxa [ 13] thia [1,14,25] triazatetracyclo [14.7.2.0-3,6 ~ .0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one To a solution of 13 ', 13'-dioxide (0.250 g, 0.322 mmol) was added calcium carbonate (0.161 g, 1.610 mmol), water (3.00 mL), and iodine methane (0.250 mL, 4.02 mmol). The resulting mixture was heated at 40 ° C. for 20 hours. The reaction was partitioned between water (20 mL) and DCM (50 mL). The aqueous layer was extracted with DCM (30 mL. The combined organic layers were dried over MgSO ₄ , filtered and concentrated. Purified by column chromatography (24 g of silica; 0% to 30% acetone in heptane) (1S , 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-methoxy-12 '-(2-methoxyethyl) -11'-methyl-15' Oxo-3,4-dihydro-2H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14,25] triazatetracyclo [14.7.2.0-3,6]. 0-19,24-] pentacosa [8,16,18,24] tetraene] -7'-carbaldehyde 13 ', 13'-dioxide was obtained as a white solid (0.130 g) ¹ H NMR (D Chloromethane-d2) δ 9.74 (s, 1H), 9.50 (s, 1H), 7.72 (d, J = 8.4 Hz, 1H), 7.47 (d, J = 7.8 Hz, 1H), 7.21 (d, J = 8.0 Hz, 2H), 7.12 (d, J = 2.2 Hz, 1H), 5.69 (d, J = 16.2 Hz, 1H), 5.38-5.47 (m, 1H), 4.42 (dd, J = 14.0, 8.5 Hz, 1H), 4.19 (d, J = 12.3 Hz, 1H), 4.04 (d, J = 12.1 Hz, 1H), 3.87 (d, J = 14.7 Hz, 1H), 3.60 (td, J = 8.7, 4.9 Hz, 1H), 3.46-3.54 (m, 2H), 3.38-3.45 (m, 1H), 3.31 (s, 3H ), 3.06 (s, 3H), 2.96 (dd, J = 14.1, 5.9 Hz, 1H), 2.74-2.90 (m, 4H), 2.46 (ddd, J = 11.2, 7.1, 3.7 Hz, 1H), 2.21- 2.28 (m, 1H), 2.11-2.20 (m, 1H), 1.97-2.08 (m, 2H), 1.81-1.96 (m, 5H), 1.67-1.79 (m, 1H), 1.55-1.66 (m, 1H ), 1.40-1.50 (m, 1H), 1.14 (d, J = 6.8 Hz, 3H) MS (ESI, cation) m / z 686.2 (M + H) ⁺ .

Step 7: (1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7 '-((9aS) -hexahydropyrazino [2,1-c] [1,4] oxazine-8 (1H) -ylmethyl) -7'-methoxy-12 '-(2-methoxyethyl) -11'-methyl-3,4-dihydro-2H, 15' H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14,25] triazatetracyclo [14.7.2.0-3,6-0.0-19,24-] pentacosa [ 8,16,18,24] tetraene] -15'-on 13 ', 13'-dioxide

(1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-methoxy-12 '-(2-methoxyethyl) in DCM (4.0 mL) -11'-Methyl-15'-oxo-3,4-dihydro-2H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14,25] triazatetracyclo [14.7 .2.0-3,6-0.0-19,24-] of pentacosa [8,16,18,24] tetraene] -7'-carbaldehyde 13 ', 13'-dioxide (0.080 g, 0.117 mmol) To the solution was added (S) -octahydropyrazino [2,1-c] [1,4] oxazine (0.093 g, 0.653 mmol) and acetic acid (1 drop) in DCM (4.0 mL). The mixture was stirred at room temperature under nitrogen atmosphere for 1 hour. Sodium triacetoxyborohydride (0.100 g, 0.472 mmol) was added and the mixture was stirred at rt for 1 h. The reaction was partitioned between water (10 mL) and DCM (20 mL). The aqueous layer was extracted with DCM (20 mL. The combined organic layers were dried over MgSO ₄ , filtered and concentrated. Purified by column chromatography (24 g silica; 0-30% MeOH in heptane) (1S). , 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7 '-((9aS) -hexahydropyrazino [2,1-c] [1,4] Oxazine-8 (1H) -ylmethyl) -7'-methoxy-12 '-(2-methoxyethyl) -11'-methyl-3,4-dihydro-2H, 15'H-spiro [naphthalene -1,22 '-[20] oxa [13] thia [1,14,25] triazatetracyclo [14.7.2.0-3,6-0.0-19,24-] pentacosa [8,16,18 , 24] tetraen] -15'-one 13 ', 13'-dioxide was obtained as a white solid (0.066 g) ¹ H NMR (dichloromethane-d2) δ 7.70 (d, J = 8.4 Hz, 1H ), 7.40 (d, J = 7.8 Hz, 1H), 7.19 (d, J = 8.4 Hz, 1H), 7.08-7.16 (m, 2H), 5.53-5.66 (m, 2H), 4.13-4.19 (m, 1H), 4.02-4.12 (m, 2H), 3.74-3.83 (m, 2H), 3.65-3.73 (m, 1H), 3.53-3.63 (m, 3H), 3.46 (d, J = 14.7 Hz, 1H) , 3.32 (s, 4H), 2.98-3.10 (m, 7H), 2.74-2.85 (m, 2H), 2.72 (d, J = 6 .1 Hz, 1H), 2.52-2.64 (m, 3H), 2.46 (d, J = 16.8 Hz, 3H), 2.23-2.37 (m, 2H), 2.06-2.15 (m, 1H), 1.96-2.03 ( m, 2H), 1.85-1.94 (m, 4H), 1.72-1.81 (m, 2H), 1.45-1.63 (m, 6H), 1.08 (d, J = 6.8 Hz, 3H) No exchangeable protons were observed MS (ESI, cation) m / z 812.4 (M + H) ⁺ .

Example 21

(1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-Chloro-7'-methoxy-12 '-(2-methoxyethyl) -11'-methyl- 7 '-((9aR) -octahydro-2H-pyrido [1,2-a] pyrazin-2-ylmethyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14,25] triazatetracyclo [14.7.2.0-3,6-0.0-19,24-] pentacosa [8,16,18,24] tetra EN] -15'-one 13 ', 13'-dioxide

(1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-methoxy-12 '-(2-methoxyethyl) in DCM (5.0 mL) -11'-Methyl-15'-oxo-3,4-dihydro-2H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14,25] triazatetracyclo [14.7 .2.0-3,6-0.0-19,24-] of pentacosa [8,16,18,24] tetraene] -7'-carbaldehyde 13 ', 13'-dioxide (0.140 g, 0.204 mmol) To the solution was added (R) -octahydro-1H-pyrido [1,2-a] pyrazine (0.160 g, 1.141 mmol) and AcOH (2 drops) in DCM (1 mL). The mixture was stirred at room temperature under nitrogen for 1 hour and then treated with sodium triacetoxyborohydride (0.173 g, 0.816 mmol). The resulting mixture was stirred for 1 h and then partitioned between water (10 mL) and DCM (20 mL). The aqueous layer was extracted with DCM (20 mL. The combined organic layers were dried over MgSO ₄ , filtered and concentrated. Purified by column chromatography (24 g silica; 0% to 10% MeOH in DCM) (1S , 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-methoxy-12 '-(2-methoxyethyl) -11'-methyl-7' -((9aR) -octahydro-2H-pyrido [1,2-a] pyrazin-2-ylmethyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'- [20] oxa [13] thia [1,14,25] traazatetracyclo [14.7.2.0-3,6-0.0 ~ 19,24] pentacosa [8,16,18,24] tetraene -15'-one 13 ', 13'-dioxide was obtained as a white solid (0.120 g) ¹ H NMR (dichloromethane-d2) δ 7.69-7.76 (m, 1H), 7.42-7.50 (m, 1H ), 7.18 (dd, J = 8.5, 2.1 Hz, 1H), 7.04-7.14 (m, 2H), 5.77 (br. S., 2H), 4.17 (d, J = 12.9 Hz, 1H), 4.00-4.13 (m, 2H), 3.77 (d, J = 14.5 Hz, 1H), 3.64-3.73 (m, 1H), 3.57 (d, J = 9.2 Hz, 2H), 3.35-3.47 (m, 1H), 3.21- 3.34 (m, 5H), 3.09 (br. S., 3H), 2.99 (br. S., 1H), 2.83-2.95 ( m, 2H), 2.65-2.82 (m, 5H), 2.55 (br. S., 2H), 2.25-2.44 (m, 3H), 2.09-2.21 (m, 1H), 1.97-2.08 (m, 3H) , 1.89 (d, J = 19.2 Hz, 4H), 1.61-1.73 (m, 4H), 1.38-1.51 (m, 4H), 1.29-1.35 (m, 1H), 1.17 (br. S., 2H), 1.02 (d, J = 6.8 Hz, 4H) No exchangeable protons observed MS (ESI, cation) m / z 810.4 (M + H) ⁺ .

Example 33

(1S, 3'R, 6'R, 7'R, 8'E, 12'R) -6-Chloro-12'-ethyl-7'-methoxy-14'-methyl-7 '-((9aR ) -Octahydro-2H-pyrido [1,2-a] pyrazin-2-ylmethyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraen] -15'-one 13 ', 13'-dioxide

Step 1: (1S, 3'R, 6'R, 7'R, 8'E, 12'R) -6-Chloro-12'-ethyl-7'-methoxy-14'-methyl-15'- Oxo-3,4-dihydro-2H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazettracyclo [14.7.2.0-3,6-0.0-19 , 24 ~] pentacosa [8,16,18,24] tetraene] -7'-carbaldehyde 13 ', 13'-dioxide

Two-drum vials (1S, 3'R, 6'R, 7'R, 8'E, 12'R) -6-chloro-7 '-(1,3-dithiane-2-yl) -12 '-Ethyl-7'-methoxy-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-[20] oxa [13] thia [1,14] diazatracyclo [ 14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ', 13'-dioxide (27 mg, 0.037 mmol; ( R ¹ = H and (S) -6'-chloro-5-(((1R, 2R) -2-((S) -1-hydroxyallyl) cyclobutyl) methyl) -3 ', 4,4 ', 5-tetrahydro-2H, 2'H-spiro [benzo [b] [1,4] oxazepine-3,1'-naphthalene] -7-carboxylic acid and (R) -hept-6-ene-3 -Approached via General Method 1 (using sulfonamide) and General Method 5 (using MeI), magnetic stir bar, acetonitrile (820 μL) and water (205 μL). To the resulting suspension was added calcium carbonate (18.5 mg, 0.185 mmol) and iodine methane (23 μL, 0.37 mmol). The vial was sealed and the mixture was stirred at 45 ° C. After 2.5 hours, 19 hours, 23 hours, and 27 hours additional iodine methane (10 equiv) was added. After 51 hours of reaction time, the reaction was quenched by addition of saturated aqueous ammonium chloride (1 mL) and water (1 mL). The mixture was washed with EtOAc (3 x 2 mL) and the combined organic extracts washed with salt, dried over magnesium sulfate, filtered and concentrated under reduced pressure (1S, 3'R, 6'R, 7'R, 8'E, 12'R) -6-Chloro-12'-ethyl-7'-methoxy-15'-oxo-3,4-dihydro-2H-spiro [naphthalene-1,22 '-[20] Oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraene] -7'-carb Aldehyde 13 ', 13'-dioxide and (1S, 3'R, 6'R, 7'R, 8'E, 12'R) -6-chloro-12'-ethyl-7'-methoxy-14'-Methyl-15'-oxo-3,4-dihydro-2H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diaza tetracyclo [14.7.2.0-3, 6 ~ .0 ~ 19,24 ~] Pentacosa [8,16,18,24] tetraene] -7'-carbaldehyde 13 ', 13'-dioxide is obtained in a ratio of 3: 1, which is further purified. Used in the next step without.

Step 2: (1S, 3'R, 6'R, 7'R, 8'E, 12'R) -6-Chloro-12'-ethyl-7'-methoxy-14'-methyl-7'- ((9aR) -octahydro-2H-pyrido [1,2-a] pyrazin-2-ylmethyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[ 20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraen] -15 ' -On 13 ', 13'-dioxide

1 mL vial (1S, 3'R, 6'R, 7'R, 8'E, 12'R) -6-chloro-12'-ethyl-7'-methoxy-15'-oxo-3, 4-dihydro-2H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diaza tetracyclo [14.7.2.0-3,6-0.0-19,24] Pentacosa [8,16,18,24] tetraene] -7'-carbaldehyde with 13 ', 13'-dioxide and (1S, 3'R, 6'R, 7'R, 8'E, 12'R ) -6-chloro-12'-ethyl-7'-methoxy-14'-methyl-15'-oxo-3,4-dihydro-2H-spiro [naphthalene-1,22 '-[20] oxa [ 13] thia [1,14] diazettracyclo [14.7.2.0-3,6-0.0-19,24-] pentacosa [8,16,18,24] tetraene] -7'-carbaldehyde 13 3: 1 mixture of ', 13'-dioxide (0.222 g, 0.034 mmol), (R) -octahydro-1H-pyrido [1,2-a] pyrazine (26.5 mg, 0.189 mmol; Aurum Pharmatech, Franklin Park , New Jersey), magnetic stir bars, and 1,2-dichloroethane (343 μL). The resulting mixture was stirred for 1 h, then sodium triacetoxyborohydride (3.6 mg, 0.017 mmol) was added. After 45 minutes, sodium triacetoxyborohydride (3.6 mg, 0.017 mmol) was added for the second time, and the reaction was continued for 2 hours, followed by sodium triacetoxyborohydride (3.6 mg, 0.017 mmol). Third addition. After 3 hours more, the reaction was quenched by the addition of methanol. (1S, 3'R, 6'R, 7'R, 8'E, 12'R) -6-Chloro-12'-ethyl-7'-methoxy-14'-methyl-7 '-((9aR ) -Octahydro-2H-pyrido [1,2-a] pyrazin-2-ylmethyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatrocyclo [14.7.2.0-3,6 ~ .0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ', 13'-dioxide was converted to RP-HPLC (column: Phenomenex Luna, C18, 150 x 21 mm; solvent: A = water (0.1% TFA), B = (R) (0.1% TFA), 30 mL / min Purified from 30% B to 100% B over 18 minutes, then 100% B) for 2 minutes and then isolated as the corresponding TFA salt (5.2 mg, 0.006 mmol, 17% yield); MS (ESI, cation) m / z 779.3 (M + H) ⁺ .

Example 34

(1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-methoxy-11 ', 12'-dimethyl-7'-(((2 -(4-morpholinyl) ethyl) amino) methyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] Diazatetracyclo [14.7.2.0 ~ 3,6 ~ .0 ~ 19,24 ~] Pentacosa [8,16,18,24] tetraene] -15'-one 13 ', 13'-dioxide

General method 13

(1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-11 ', 12'-dimethyl-15'-oxo-7'-methoxy-3, 4-dihydro-2H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diaza tetracyclo [14.7.2.0-3,6-0.0-19,24] Pentacosa [8,16,18,24] tetraene] -7'-carbaldehyde 13 ', 13'-dioxide (52 mg, 0.081 mmol) and 2-morpholinoethanamine (106 μL) in THF (810 μL) μL, 0.811 mmol) was stirred at ambient temperature for 90 minutes. Sodium cyanotrihydroborate (25.5 mg, 0.405 mmol) and acetic acid (93 μL, 1.6 mmol) were added and the reaction mixture was stirred at ambient temperature for 1 hour. The reaction mixture was diluted with EtOAc (2 mL) and washed with saturated aqueous sodium bicarbonate (5 mL); The layers were separated and the aqueous layer was washed with EtOAc (2 x 5 mL). The organic extracts were combined, dried over anhydrous MgSO ₄ , filtered and concentrated in vacuo to afford an off-white solid. (1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-methoxy-11 ', 12'-dimethyl-7'-(((2 -(4-morpholinyl) ethyl) amino) methyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] Diazatetracyclo [14.7.2.0 ~ 3,6 ~ .0 ~ 19,24 ~] Pentacosa [8,16,18,24] tetraene] -15'-one 13 ', 13'-dioxide RP- HPLC (Column: Phenomenex Luna, C18, 150 x 21 mm; Solvent: A = Water (0.1% TFA), B = (R) (0.1% TFA), 30 mL / min, 100 at 30% B over 18 minutes Purified to 100% B) then up to% B and then isolated as corresponding TFA salt (41.8 mg, 0.048 mmol, 59% yield); MS (ESI, cation) m / z 755.2 (M + H) ⁺ .

Example 99

(1S, 3'R, 6'R, 7'S, 8'E, 9a ''S, 11'S, 12'R) -6-chloro-11', 12'-dimethyl-3,4,6 '', 7 '', 9 '', 9a ''-hexahydro-1''H, 2H, 15'H-dispiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diamond Zatetracyclo [14.7.2.0 ~ 3,6 ~ .0 ~ 19,24 ~] Pentacosa [8,16,18,24] tetraene-7 ', 3' '-[1,4] oxazino [3 , 4-c] [1,4] oxazine] -15'-one 13 ', 13'-dioxide

Step 1: (1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-7 '-(((3R) -3- (hydroxy Oxymethyl) -4-morpholinyl) methyl) -11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-[20] oxa [13 ] Thia [1,14] diaza tetracyclo [14.7.2.0-3,6-0.0-19,24-] pentacosa [8,16,18,24] tetraene] -15'-one 13 ', 13'-dioxide

(1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-11 ', 12'-dimethyl-15'-oxo-3, 4-dihydro-2H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diaza tetracyclo [14.7.2.0-3,6-0.0-19,24] Pentacosa [8,16,18,24] tetraene] -7'-carbaldehyde 13 ', 13'-dioxide (0.050 g, 0.080 mmol) and (R) -morpholin-3-ylmethanol hydrochloride (0.124 g, 0.807 mmol; N, N-diisopropylethylamine (0.230 mL, 1.32 mmol) was added via syringe to a room temperature mixture of J & W Pharmlab, Levittown, Pennsylvania. After 30 minutes, 1.0 M sodium cyanoborohydride and acetic acid (0.100 mL, 1.73 mmol) in tetrahydrofuran (0.400 mL, 0.400 mmol) were added and the reaction was stirred at rt overnight. The reaction mixture was quenched with saturated NH ₄ Cl and the aqueous layer was extracted with DCM (3 ×). The combined organic layers were evaporated onto silica gel and purified by flash chromatography eluting with 0% to 100% 2M NH ₃ dissolved in DCM to give 70 mg (1S, 3'R, 6'R, 7'S, 8). 'E, 11'S, 12'R) -6-chloro-7'-hydroxy-7'-(((3R) -3- (hydroxymethyl) -4-morpholinyl) methyl) -11 ', 12 '-Dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-[20] oxa [13] thia [1,14] diaza tetracyclo [14.7.2.0-3] , 6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraen] -15'-one 13 ', 13'-dioxide was obtained as a white crystalline solid. (ESI, cation) m / z 728.3 (M + l) ⁺ .

Step 2: (1S, 3'R, 6'R, 7'S, 8'E, 9a ''S, 11'S, 12'R) -6-chloro-11', 12'-dimethyl-3,4,6 '', 7 '', 9 '', 9a ''-hexahydro-1''H, 2H, 15'H-dicespiro [naphthalene-1,22 '-[20] oxa [13] thia [1, 14] diatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraene-7 ', 3' '-[1,4] oxa Zino [3,4-c] [1,4] oxazine] -15'-one 13 ', 13'-dioxide

In tetrahydrofuran (1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-7 '-(((3R) -3- ( Hydroxymethyl) -4-morpholinyl) methyl) -11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-[20] oxa [ 13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraen] -15'-one 13 ' To a room temperature solution of 0.3'-dioxide (0.3 mL) was added 60% sodium hydride (0.011 g, 0.275 mmol) in mineral oil as a solid. After 30 minutes, the mixture was cooled (0 ° C.) and treated with 1- (p-toluenesulfonyl) imidazole (0.064 g, 0.288 mmol) and the reaction was allowed to warm to room temperature overnight. The reaction mixture was quenched with saturated NH ₄ Cl and the aqueous layer was extracted with EtOAc (3 ×). The combined organic layers were evaporated onto silica gel and purified by flash chromatography (Isco, (4 g of HP)) eluting with 2 M NH ₃ in (MeOH: CH ₂ Cl ₂ (0: 1 → 1: 9)). (1S, 3'R, 6'R, 7'S, 8'E, 9a ''S, 11'S, 12'R) -6-chloro-11', 12'-dimethyl-3,4,6 '',7'',9'',9a''-hexahydro-1''H, 2H, 15'H-dicespiro [naphthalene-1,22'-[20] oxa [13] thia [1,14 ] Diazatetracyclo [14.7.2.0 ~ 3,6 ~ .0 ~ 19,24 ~] Pentacosa [8,16,18,24] tetraene-7 ', 3''-[1,4] oxazino [3,4-c] [1,4] oxazine] -15'-one 13 ', 13'-dioxide was obtained as a tan crystalline solid (2.1 mg, 9%). MS (ESI, cation) m / z 710.3 (M + l) ⁺ .

Example 100

(1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-7 '-(((3S) -3- (1H-imidazole -1-ylmethyl) -4-morpholinyl) methyl) -11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-[20] Oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraen] -15'-one 13 ', 13'-dioxide

Step 1: (1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-7 '-(((3S) -3- (hydroxy Oxymethyl) -4-morpholinyl) methyl) -11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-[20] oxa [13 ] Thia [1,14] diaza tetracyclo [14.7.2.0-3,6-0.0-19,24-] pentacosa [8,16,18,24] tetraene] -15'-one 13 ', 13'-dioxide

(1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-11 ', 12'-dimethyl-15'-oxo-3, 4-dihydro-2H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diaza tetracyclo [14.7.2.0-3,6-0.0-19,24] Pentacosa [8,16,18,24] tetraene] -7'-carbaldehyde 13 ', 13'-dioxide (0.052 g, 0.083 mmol) and 3 (S) -hydroxy in tetrahydrofuran (2 mL) N, N-diisopropylethylamine (0.250 mL, 1.437 mmol) was added to a room temperature mixture of methylmorpholine (0.099 g, 0.845 mmol; Levittown, J & W Pharmlab, Pennsylvania). After 1 h, 1.0 M sodium cyanoborohydride (0.450 mL, 0.450 mmol) and acetic acid (0.100 mL, 1.73 mmol) in tetrahydrofuran were added and the reaction stirred overnight. The reaction mixture was quenched with pH 7 buffer and the aqueous layer was extracted with DCM (3 ×). The combined organic layers were evaporated onto silica gel and purified by flash chromatography (Isco (4 g)) (eluted with 25% EtOH / EtOAc: heptanes (0: 1 → 1: 1)) (1S, 3 'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-7'-(((3S) -3- (hydroxymethyl) -4-mo Polyyl) methyl) -11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-[20] oxa [13] thia [1,14] Diazatetracyclo [14.7.2.0 ~ 3,6 ~ .0 ~ 19,24 ~] Pentacosa [8,16,18,24] tetraene] -15'-one 13 ', 13'-dioxide Obtained as a crystalline solid (46 mg, 76%). (ESI, cation) m / z 728.2 (M + l) ⁺ .

Step 2: (1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-7 '-(((3S) -3- (1H -Imidazol-1-ylmethyl) -4-morpholinyl) methyl) -11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'- [20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraene] -15 '-On 13', 13'-dioxide

In tetrahydrofuran (1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-7 '-(((3S) -3- ( Hydroxymethyl) -4-morpholinyl) methyl) -11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-[20] oxa [ 13] thia [1,14] diatetracyclo [14.7.2.0-3,6-0.0-19,24-] pentacosa [8,16,18,24] tetraene] -15'-one 13 ' To a room temperature solution (1 mL) of 13'-dioxide, sodium hydride (0.020 g, 0.51 mmol) was added as a solid. After 30 minutes, the reaction was cooled (0 ° C.) and treated with 1- (p-toluenesulfonyl) imidazole (0.112 g, 0.505 mmol). After stirring overnight, the reaction mixture was quenched with pH 7 buffer and the aqueous layer was extracted with DCM (3 ×). The combined organic layers were evaporated onto silica gel and purified by flash chromatography (Isco (4 g)) (eluting with 25% EtOH / EtOAc: heptanes (0: 1 → 1: 0)) (1S, 3 'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-7'-(((3S) -3- (1H-imidazol-1-yl Methyl) -4-morpholinyl) methyl) -11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-[20] oxa [13] Thia [1,14] diaza tetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraen] -15'-one 13 ', 13 '-Dioxide was obtained as a white crystalline solid (27 mg, 55%). (ESI, cation) m / z 778.3 (M + l) ⁺ .

Example 105

(1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -7'-ethoxy-7 '-((9aS) -hexahydropyrazino [2,1-c] [ 1,4] oxazen-8 (1H) -ylbetayl) -11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-[20] Oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraen] -15'-one 13 ', 13'-dioxide

(1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-ethoxy-7 '-((9aS) -hexahydro in EtOAc (1 mL) Pyrazino [2,1-c] [1,4] oxazine-8 (1H) -ylmethyl) -11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [ Naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6-0.0-19,24-] pentacosa [8,16,18, Tetraen] -15'-one 13 ', 13'-dioxide (0.010 g, 0.013 mmol) and palladium in activated carbon (10 wt% dry Degussa type on a dry basis; 0.005 g, 2.3 μmol) ) Was stirred overnight at room temperature under nitrogen (18 psig). The reaction was filtered through a pad of celite and the pad was washed with EtOAc. The filtrate was concentrated under reduced pressure, diluted with MeOH, eluted with 0.1% TFA-H ₂ O: 0.1% TFA CH ₃ CN (9: 1 to 1: 9) reversed phase HPLC (Gilson; Gemini-NX C18 AXIA, 100 x 50 mm column). Fractions containing the desired product were combined and partitioned into pH 7 buffer (1 MK ₂ HPO ₄ / KH ₂ PO ₄ ) / EtOAc. The aqueous layer was extracted with EtOAc (3 ×) and the combined organic layers were washed with brine, dried over Na ₂ SO ₄ and filtered. The filtrate was concentrated under reduced pressure to afford (1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -7'-ethoxy-7 '-((9aS) -hexahydropyrazino [2]. , 1-c] [1,4] oxazine-8 (1H) -ylmethyl) -11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1, 22 '-[20] oxa [13] thia [1,14] diazatetrocyclo [14.7.2.0-3,6-0.0-19,24-] pentacosa [8,16,18,24] tetra EN] -15'-one 13 ', 13'-dioxide was obtained as a white crystalline solid (6.5 mg, 68%). (ESI, cation) m / z 747.3 (M + l) ⁺ .

Example 124

(1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-4 '', 11 ', 12'-trimethyl-3,4-dihydro-2H, 15 'H-dicespiro [naphthalene-1,22'-[20] oxa [13] thia [1,14] diazetcyclocyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraene-7 ', 2' '-[1,4] oxazinane] -15'-one 13', 13'-dioxide

Step 1: (1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-11 ', 12'-dimethyl-15' Oxo-3,4-dihydro-2H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diaza tetracyclo [14.7.2.0-3,6-0.0 ... 19,24-] pentacosa [8,16,18,24] tetraene] -7'-carbaldehyde 13 ', 13'-dioxide and (1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-Chloro-7'-hydroxy-11 ', 12'-dimethyl-15'-oxo-3,4-dihydro-2H-spiro [naphthalene-1,22'-[ 20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraen] -7 ' Carbaldehyde 13 ', 13'-dioxide

(1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7 '-(1,3-dithiane-2-yl) -7'-hydro Roxy-11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraene] -15'-13 ', 13'-dioxide and 50 ° C acetonitrile ( (1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7 '-(1,3-dithiane-2) in 44 mL) / water (6.5 mL) -Yl) -7'-hydroxy-11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-[20] oxa [13] thia [ 1,14] diatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraene] -15'-one 13 ', 13'- To a solution of dioxide (2.66 g, 3.71 mmol) was added sequentially calcium carbonate (2.60 g, 18. 5 mmol) and iodine methane (1M in TMBE; 18.5 mL, 37.1 mmol); The reaction mixture was stirred at 50 ° C. for 16 h. The slurry was filtered to remove any excess calcium carbonate and the filtrate was concentrated. Dilute solid with EtOAc (150 mL); Pour out the milky mixture; The remaining solid was diluted with DCM / IPA (3: 2, 200 mL) and the combined organics were partitioned with saturated aqueous NH ₄ Cl (100 mL). The organic layer was separated, solubilized with MeOH, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude product was absorbed onto silica gel and purified via automated flash chromatography (silica gel; 0% to 50% EtOAc in 0.3 heptanes containing 0.3% AcOH) in (1S, 3'R, 6'R, 7). 'R, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-11', 12'-dimethyl-15'-oxo-3,4-dihydro-2H-spiro [naphthalene -1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6-0.0-19,24-] pentacosa [8,16,18,24 ] Tetraene] -7'-carbaldehyde 13 ', 13'-dioxide (396 mg, 0.631 mmol, 17% yield) and (1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12' R) -6-chloro-7'-hydroxy-11 ', 12'-dimethyl-15'-oxo-3,4-dihydro-2H-spiro [naphthalene-1,22'-[20] oxa [ 13] thia [1,14] diazettracyclo [14.7.2.0-3,6-0.0-19,24-] pentacosa [8,16,18,24] tetraene] -7'-carbaldehyde 13 All ', 13'-dioxide (0.810, 1.29 mmol, 35% yield) was obtained as a white solid. MS (ESI, + ve) m / z 627.2 (M + 1) ⁺ for both.

Step 2: (1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-11 ', 12'-dimethyl-7'-( (Methylamino) methyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0 ~ 3,6 ~ .0 ~ 19,24 ~] Pentacosa [8,16,18,24] tetraene] -15'-on 13 ', 13'-dioxide

(1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-11 ', 12'-dimethyl-15'-oxo-3, 4-dihydro-2H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diaza tetracyclo [14.7.2.0-3,6-0.0-19,24] Pentacosa [8,16,18,24] tetraene] -7'-carbaldehyde 13 ', 13'-dioxide (48 mg, 0.077 mmol), methaneamine hydrochloride (91 mg, 1.3 mmol), and DCM (383) a mixture of DIPEA (227 μL, 1.30 mmol) in μL) / MeOH (580 μL) was stirred at room temperature for 15 minutes; Sodium cyanotrihydroborate (14 mg, 0.23 mmol) was added. The slurry was stirred at room temperature for 30 minutes. The reaction mixture was diluted with DCM (50 mL) and added to a separatory funnel and washed with water (50 mL); The organic layer was separated, dried over anhydrous Na ₂ SO ₄ , and concentrated in vacuo. The crude product was adsorbed onto silica gel and purified via automated flash chromatography (silica gel; 0% to 25% MeOH in DCM) (1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-Chloro-7'-hydroxy-11 ', 12'-dimethyl-7'-((methylamino) methyl) -3,4-dihydro-2H, 15'H- Spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6-0.0-19,24-] pentacosa [8,16, 18,24] tetraen] -15'-one 13 ', 13'-dioxide was obtained as a white film (14 mg, 0.022 mmol, 29% yield). MS (ESI, + ve) m / z 642.2 (M + l) ⁺ .

Step 3: (1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-Chloro-4 '', 11 ', 12'-trimethyl-3,4-dihydro- 2H, 15'H-dicespiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazetcyclocyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~ ] Pentacosa [8,16,18,24] tetraene-7 ', 2' '-[1,4] oxazinane] -15'-one 13', 13'-dioxide

(1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-11 ', 12'-dimethyl-7 in DMF (0.22 mL) '-((Methylamino) methyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-[20] oxa [13] thia [1,14] diazatetracyclo [ 14.7.2.0-3,6--0.19-24]] pentacosa [8,16,18,24] tetraene] -15'-one 13 ', 13'-dioxide (14 mg, 0.022 mmol) To a solution of 1,2-dibromoethane (8 μL, 0.09 mmol) was added calcium carbonate (85 mg, 0.26 mmol) at ambient temperature. The reaction mixture was stirred at 70 ° C. for 16 h. 1-tosyl-1H-imidazole (4.8 mg, 0.022 mmol) and sodium hydride (60% in mineral oil; 0.5 mg, 0.02 mmol) were added to the reaction mixture and then stirred at ambient temperature for 20 minutes. The reaction mixture was diluted with EtOAc (50 mL), added to a separatory funnel and washed twice with saturated aqueous sodium bicarbonate (50 mL); The organic layer was separated, dried over anhydrous Na 2 SO 4 and concentrated in vacuo. The crude product was adsorbed onto silica gel and purified via automated flash chromatography (silica gel; 0% to 10% MeOH in DCM) to give (1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-Chloro-4 '', 11 ', 12'-trimethyl-3,4-dihydro-2H, 15'H-dispiro [naphthalene-1,22'-[20] oxa [13] thia [1,14] diazetcyclocyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraene-7 ', 2''-[1,4] oxazinane] -15'-one 13', 13'-dioxide was obtained as a pale yellow oil (2 mg, 3 μmol, 14% yield). MS (ESI, + ve) m / z 668.3 (M + l) ⁺ .

Example 125

(1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -7 '-((tert-butylamino) methyl) -6-chloro-7'-hydroxy-11' , 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0 ~ 3,6 ~ .0 ~ 19,24 ~] Pentacosa [8,16,18,24] tetraene] -15'-on 13 ', 13'-dioxide

(1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-11 ', 12'-dimethyl-15'-oxo-3, 4-dihydro-2H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diaza tetracyclo [14.7.2.0-3,6-0.0-19,24] Pentacosa [8,16,18,24] tetraene] -7'-carbaldehyde 13 ', 13'-dioxide (99 mg, 0.16 mmol) and 2-methylpropan-2-amide in THF (1.6 mL) 115 mg, 1.58 mmol) is stirred at ambient temperature for 1.5 hours; Sodium cyanotrihydroborate (50 mg, 0.79 mmol) and acetic acid (181 μL, 3.16 mmol) were added and the reaction mixture was stirred at ambient temperature for 1 hour. The reaction mixture was diluted with EtOAc (75 mL), added to a separatory funnel and washed with saturated aqueous sodium bicarbonate (100 mL); The organic layer was separated, dried over anhydrous Na ₂ SO ₄ , and concentrated in vacuo. The crude product was adsorbed onto silica gel and purified via automated flash chromatography (silica gel; 0% to 10% MeOH in DCM) to give (1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -7 '-((tert-butylamino) methyl) -6-chloro-7'-hydroxy-11', 12'-dimethyl-3,4-dihydro-2H, 15 ' H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6-0.0-19,24-] pentacosa [8, 16,18,24] tetraen] -15'-one 13 ', 13'-dioxide was obtained as a white solid (53 mg, 0.077 mmol, 49% yield). MS (ESI, + ve) m / z 684.3 (M + l) ⁺ .

Example 126

(1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-7 '-(((2-hydroxyethyl) (1-methyl Ethyl) amino) methyl) -11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-[20] oxa [13] thia [1,14 ] Diazatetrocyclo [14.7.2.0 ~ 3,6 ~ .0 ~ 19,24 ~] Pentacosa [8,16,18,24] tetraene] -15'-one 13 ', 13'-dioxide

(1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-11 ', 12'-dimethyl-15'-oxo-3, 4-dihydro-2H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diaza tetracyclo [14.7.2.0-3,6-0.0-19,24] Pentacosa [8,16,18,24] tetraene] -7'-carbaldehyde 13 ', 13'-dioxide (68 mg, 0.11 mmol) and 2- (isopropylamino) ethanol in THF (1.1 mL) Enamine, Monmouth Jct, NJ; 112 mg, 1.08 mmol) was stirred at ambient temperature for 2.5 hours; Sodium cyanotrihydroborate (34 mg, 0.54 mmol) and acetic acid (0.1 mL, 2.2 mmol) were added and the reaction mixture was stirred at ambient temperature for 1 hour. The reaction mixture was diluted with EtOAc (75 mL), added to a separatory funnel and washed with saturated aqueous sodium bicarbonate (100 mL); The organic layer was separated, dried over anhydrous Na ₂ SO ₄ , and concentrated in vacuo. The crude product was adsorbed onto silica gel and purified via automated flash chromatography (silica gel; 0% to 8% MeOH in DCM) (1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-Chloro-7'-hydroxy-7 '-(((2-hydroxyethyl) (1-methylethyl) amino) methyl) -11', 12'-dimethyl-3 , 4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diaza tetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ', 13'-dioxide was obtained as a white solid (20 mg, 0.028 mmol, 26% yield). MS (ESI, + ve) m / z 714.2 (M + l) ⁺ .

Example 127

(1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-11 ', 12'-dimethyl-4' '-(1-methylethyl) -3, 4-dihydro-2H, 15'H-dispiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraene-7 ', 2' '-[1,4] oxazinane] -15'-one 13', 13'-dioxide

(1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-7 '-(((2-hydroxy in THF (0.24 mL)) Ethyl) (1-methylethyl) amino) methyl) -11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-[20] oxa [13 ] Thia [1,14] diatetracyclo [14.7.2.0-3,6-0.0-19,24-] pentacosa [8,16,18,24] tetraene] -15'-one 13 ', To a solution of 13′-dioxide (17 mg, 0.024 mmol) and 1-tosyl-1H-imidazole (6.9 mg, 0.031 mmol) was added sodium hydride (60% in mineral oil; 3 mg, 0.07 mmol) at 0 ° C. ; The reaction mixture was stirred at 0 ° C. for 15 minutes. The reaction mixture was diluted with EtOAc (75 mL) and added to a separatory funnel and washed with saturated aqueous ammonium chloride (100 mL); The organic layer was separated, dried over anhydrous Na ₂ SO ₄ , and concentrated in vacuo. A solution of the crude product in DCM was added on the column and purified via automated flash chromatography (silica gel; 0% to 10% MeOH in DCM) (1S, 3'R, 6'R, 7'S, 8 'E, 11'S, 12'R) -6-chloro-11', 12'-dimethyl-4 ''-(1-methylethyl) -3,4-dihydro-2H, 15'H-dicespiro [ Naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6-0.0-19,24-] pentacosa [8,16,18, 24] tetraen-7 ', 2''-[1,4] oxazinane] -15'-one 13', 13'-dioxide was obtained as a white arc (6 mg, 9 μmol, 36% yield). . MS (ESI, + ve) m / z : 696.3 (M + l) ⁺ .

Example 128

(1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-11 ', 12'-dimethyl-3,4-dihydro-2H, 2' 'H, 15'H-dicespiro [naphthalene-1,22'-[20] oxa [13] thia [1,14] diazettracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~ ] Pentacosa [8,16,18,24] tetraene-7 ', 5' '-[1,3] oxazolidine] -2' ', 15'-dione 13', 13'-dioxide or ( 1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-11 ', 12'-dimethyl-3,4-dihydro-2H, 2''H, 15'H-dicespiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6-0.0-19,24-] pentacosa [8,16,18,24] tetraene-7 ', 5' '-[1,3] oxazolidine] -2' ', 15'-dione 13', 13'-dioxide

Step 1: methyl ((1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-11 ', 12'-dimethyl- 13 ', 13'-dioxido-15'-oxo-3,4-dihydro-2H-spiro [naphthalene-1,22'-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0 ~ 3,6 ~ .0 ~ 19,24 ~] Pentacosa [8,16,18,24] tetraen] -7'-yl) acetate and methyl ((1S, 3'R, 6 ' R, 7'S, 8'E, 11'S, 12'R) -6-Chloro-7'-hydroxy-11 ', 12'-dimethyl-13', 13'-dioxido-15'-oxo-3 , 4-dihydro-2H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~ ] Pentacosa [8,16,18,24] tetraene] -7'-yl) acetate

A solution of methyl acetate (0.172 mL, 2.17 mmol) in THF (1 mL) was stirred with a solution of lithium diisopropylamide (1.0 M solution in hexanes / tetrahydrofuran; 2.17 mL, 2.17 mmol) in THF (1 mL). Was added dropwise at -78 ° C. The mixture was stirred at −78 ° C. for 0.5 h, then (1S, 3'R, 6'R, 8'E, 11'S, 12'R) -6-chloro-11 ', 12' in THF (2 mL). -Dimethyl-3,4-dihydro-2H, 7'H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7. 2.0 ~ 3,6 ~ .0 ~ 19,24 ~] Pentacosa [8,16,18,24] tetraene] -7 ', 15'-dione 13', 13'-dioxide (216 mg, 0.362 mmol ) Was slowly added via syringe. The reaction mixture was stirred at −78 ° C. for 1.5 h, then warmed to room temperature and quenched with water (15 mL). The mixture was extracted with EtOAc (25 mL). The organic layer was separated, washed with 1 M aqueous HCl (15 mL), washed with brine (15 mL), dried over MgSO ₄ , filtered and concentrated in vacuo to afford methyl ((1S, 3'R, 6 '). R, 7'R, 8'E, 11'S, 12'R) -6-Chloro-7'-hydroxy-11 ', 12'-dimethyl-13', 13'-dioxido-15'-oxo -3,4-dihydro-2H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazettracyclo [14.7.2.0-3,6-0.0-19, 24 ~] pentacosa [8,16,18,24] tetraen] -7'-yl) acetate and methyl ((1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-11 ', 12'-dimethyl-13', 13'-dioxido-15'-oxo-3,4-dihydro-2H-spiro [naphthalene-1, 22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraene ] -7'-yl) acetate crude mixture (246 mg, 0.366 mmol, 101% yield) was obtained as a yellow solid which was used directly in the next step. MS (ESI, cation) m / z 671.3 (M + H) ⁺ .

Step 2: ((1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-11 ', 12'-dimethyl-13 ', 13'-dioxido-15'-oxo-3,4-dihydro-2H-spiro [naphthalene-1,22'-[20] oxa [13] thia [1,14] diazettracyclo [ 14.7.2.0-3,6--0.19-24]] pentacosa [8,16,18,24] tetraen] -7'-yl) acetic acid and ((1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-Chloro-7'-hydroxy-11 ', 12'-dimethyl-13', 13'-deoxido-15'-oxo-3,4 Dihydro-2H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6-0.0-19,24-] penta Cosa [8,16,18,24] tetraen] -7'-yl) acetic acid

Methyl ((1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-11 ', 12 in tetrahydrofuran (7 mL) '-Dimethyl-13', 13'-dioxido-15'-oxo-3,4-dihydro-2H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14 ] Diazatetracyclo [14.7.2.0 ~ 3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraen] -7'-yl) acetate and methyl ((1S, 3 'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-11', 12'-dimethyl-13 ', 13'-dioxido-15 '-Oxo-3,4-dihydro-2H-spiro [naphthalene-1,22'-[20] oxa [13] thia [1,14] diazettracyclo [14.7.2.0-3,6-0.0 Lithium hydride (aq. 2.0 M, 0.453 mL, 0.905) in a stirred solution of pentacosa [8,16,18,24] tetraen] -7'-yl) acetate (243 mg, 0.362 mmol) mmol) was added. The reaction mixture was stirred at rt for 16 h. The reaction mixture was quenched with saturated aqueous NH ₄ Cl (30 mL) and extracted three times with EtOAc (50 mL). The combined organic layers were washed with brine (50 mL), dried over MgSO ₄ , filtered and concentrated in vacuo. The residue was purified by chromatography (silica gel; 0% to 100% EtOAc in heptane with 0.3% AcOH as a modifier) to afford the desired product contaminated with AcOH. The isolated product was azeotropically mixed with toluene ((1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-11 ', 12 '-Dimethyl-13', 13'-dioxido-15'-oxo-3,4-dihydro-2H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14 ] Diazatetracyclo [14.7.2.0 ~ 3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraen] -7'-yl) acetic acid and ((1S, 3 ' R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-11 ', 12'-dimethyl-13', 13'-dioxido-15 ' Oxo-3,4-dihydro-2H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diaza tetracyclo [14.7.2.0-3,6-0.0 ... A mixture of 19,24-] pentacosa [8,16,18,24] tetraen] -7'-yl) acetic acid (66 mg, 0.100 mmol, 27.7% yield) was obtained as a white solid. MS (ESI, cation) m / z 657.2 (M + H) ⁺ .

Step 3: (1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-11 ', 12'-dimethyl-3,4-dihydro-2H , 2''H, 15'H-dicespiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazettracyclo [14.7.2.0-3,6 ~ .0 ~ 19 , 24 ~] pentacosa [8,16,18,24] tetraene-7 ', 5' '-[1,3] oxazolidine] -2' ', 15'-dione 13', 13'- Dioxide or (1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-11 ', 12'-dimethyl-3,4-dihydro-2H, 2' 'H, 15'H-dicespiro [naphthalene-1,22'-[20] oxa [13] thia [1,14] diazettracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~ ] Pentacosa [8,16,18,24] tetraene-7 ', 5' '-[1,3] oxazolidine] -2' ', 15'-dione 13', 13'-dioxide

((1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-11 ', 12'-dimethyl-13', 13 '-Dioxido-15'-oxo-3,4-dihydro-2H-spiro [naphthalene-1,22'-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0 ~ 3,6 ~ .0 ~ 19,24 ~] Pentacosa [8,16,18,24] tetraen] -7'-yl) acetic acid and ((1S, 3'R, 6'R, 7'S, 8 'E, 11'S, 12'R) -6-chloro-7'-hydroxy-11', 12'-dimethyl-13 ', 13'-dioxido-15'-oxo-3,4-dihydro -2H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6-0.0-19,24-] pentacosa [8 Diphenylphos in a mixture of (16 mg, 0.100 mmol), triethylamine (0.031 mL, 0.221 mmol), and tert-butanol (2 mL) Poryl azide (0.024 mL, 0.110 mmol) was refluxed for 2.5 h. The reaction mixture was concentrated in vacuo. Purification of the residue by chromatography (silica gel; 0% to 100% EtOAc in heptane (containing 0.3% AcOH) as a modifier) (1S, 3'R, 6'R, 7'R, 8'E) , 11'S, 12'R) -6-chloro-11 ', 12'-dimethyl-3,4-dihydro-2H, 2''H, 15'H-dispiro [naphthalene-1,22'-[ 20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraene-7 ', 5 ''-[1,3] oxazolidine] -2 '', 15'-dione 13 ', 13'-dioxide or (1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-11 ', 12'-dimethyl-3,4-dihydro-2H, 2''H, 15'H-dispiro [naphthalene-1,22'-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraene-7 ', 5'' -[1,3] oxazolidine] -2 '', 15'-dione 13 ', 13'-dioxide was obtained as a white solid (30 mg, 0.046 mmol, 45.7% yield). MS (ESI, cation) m / z 654.2 (M + H) ⁺ .

Example 138

(1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -4 ''-benzyl-6-chloro-11 ', 12'-dimethyl-3,4-di Hydro-2H, 15'H-dicespiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 Pentacosa [8,16,18,24] tetraene-7 ', 2' '-[1,4] oxazinane] -15'-one 13', 13'-dioxide

Step 1: (1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-7 '-(((2-hydroxyethyl ) Amino) methyl) -11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-[20] oxa [13] thia [1,14] Diazatetracyclo [14.7.2.0 ~ 3,6 ~ .0 ~ 19,24 ~] Pentacosa [8,16,18,24] tetraene] -15'-one 13 ', 13'-dioxide

(1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-Chloro-7'-hydroxy-11 ', 12'-dimethyl-15'-oxo- 3,4-Dihydro-2H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6-0.0-19,24 Mixture of pentacosa [8,16,18,24] tetraene] -7'-carbaldehyde 13 ', 13'-dioxide (199 mg, 0.317 mmol) and 2-aminoethanol (322 mg, 5.27 mmol) After stirring for 20 minutes in dichloromethane (6 mL), acetic acid (0.366 mL, 6.35 mmol) and sodium cyanoborohydride (59.8 mg, 0.952 mmol) were added. The reaction mixture was stirred at rt for 17 h. The reaction mixture was quenched with saturated aqueous NH ₄ Cl (40 mL) and extracted with EtOAc (50 mL). The organic layer was separated, washed with brine (30 mL), dried over MgSO ₄ , filtered and concentrated in vacuo. The residue was purified by chromatography (silica gel; 0% to 10% ammonia dissolved in MeOH in DCM) to (1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R ) -6-chloro-7'-hydroxy-7 '-(((2-hydroxyethyl) amino) methyl) -11', 12'-dimethyl-3,4-dihydro-2H, 15'H Spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6-0.0-19,24-] pentacosa [8,16 , 18,24] tetraen] -15'-one 13 ', 13'-dioxide was obtained as a white solid (115 mg, 0.171 mmol, 53.9% yield). MS (ESI, cation) m / z 672.2 (M + H) ⁺ .

Step 2: (1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-11 ', 12'-dimethyl-3,4-dihydro-2H , 15'H-dicespiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6-0.0-19,24-] penta Cosa [8,16,18,24] tetraene-7 ', 2' '-[1,4] oxazinane] -15'-one 13', 13'-dioxide

(1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-7 '-((( 2-hydroxyethyl) amino) methyl) -11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-[20] oxa [13] thia [1,14] diaza tetracyclo [14.7.2.0-3,6-0.0-19,24-] pentacosa [8,16,18,24] tetraene] -15'-one 13 ', 13' To a stirred suspension of dioxide (115 mg, 0.171 mmol) was added sodium hydride (60% dispersion in mineral oil; 20.5 mg, 0.513 mmol) at room temperature. The mixture was stirred for 20 minutes and then cooled to 0 ° C. and then 1- (p-toluenesulfonyl) imidazole (38.0 mg, 0.171 mmol) was added. The reaction mixture was stirred at 0 ° C. for 5 hours. The reaction mixture was quenched with saturated aqueous NH ₄ Cl (20 mL) and extracted with EtOAc (30 mL). The organic layer was separated, washed with brine (20 mL), dried over MgSO ₄ , filtered and concentrated in vacuo. The residue was purified by chromatography (silica gel; 0% to 10% ammonia dissolved in MeOH in DCM) to (1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R ) -6-chloro-11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-dispiro [naphthalene-1,22'-[20] oxa [13] thia [1,14 ] Diazatetracyclo [14.7.2.0 ~ 3,6 ~ .0 ~ 19,24 ~] Pentacosa [8,16,18,24] tetraene-7 ', 2''-[1,4] oxazinane ] -15'-one 13 ', 13'-dioxide was obtained as a white solid (67 mg, 0.102 mmol, 60% yield). MS (ESI, cation) m / z 654.2 (M + H) ⁺ .

Step 3: (1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -4 ''-benzyl-6-chloro-11 ', 12'-dimethyl-3, 4-dihydro-2H, 15'H-dispiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraene-7 ', 2' '-[1,4] oxazinane] -15'-one 13', 13'-dioxide

(1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-11 ', 12'-dimethyl-3,4-dihydro-2H, 15' H-dicespiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6-0.0-19,24-] pentacosa [8 , 16,18,24] tetraen-7 ', 2''-[1,4] oxazinane] -15'-one 13', 13'-dioxide (17 mg, 0.026 mmol), (bromomethyl) Benzene (3.40 μl, 0.029 mmol), and triethylamine (7.95 μl, 0.057 mmol) were mixed in acetonitrile (0.25 mL). The reaction mixture was stirred at rt for 2 h. The reaction mixture was quenched with saturated aqueous NH ₄ Cl (10 mL) and extracted with EtOAc (15 mL). The organic layer was separated, washed with brine (10 mL), dried over MgSO ₄ , filtered and concentrated in vacuo. The residue was purified by chromatography (silica gel; 0-10% ammonia dissolved in MeOH in DCM) to give (1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R). -4 "-benzyl-6-chloro-11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-dispiro [naphthalene-1,22'-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6-0.0-19,24-] pentacosa [8,16,18,24] tetraene-7 ', 2''-[1, 4] Oxazinane] -15'-one 13 ', 13'-dioxide was obtained as a white solid (9 mg, 0.012 mmol, 47% yield) MS (ESI, cation) m / z 744.3 (M + H) ⁺ .

Example 151

(1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7 '-(2-methoxyethoxy) -11', 12'-dimethyl-7 '-((9aR) -octahydro-2H-pyrido [1,2-a] pyrazin-2-ylmethyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22' [20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraene]- 15'-on 13 ', 13'-dioxide

Step 1: (1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7 '-(1,3-dithiane-2-yl) -7'- (2-methoxyethoxy) -11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-[20] oxa [13] thia [1 , 14] diaza tetracyclo [14.7.2.0-3,6-0.0-19,24-] pentacosa [8,16,18,24] tetraene] -15'-one 13 ', 13'-dioxide

(1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7 '-(1,3-dithiane-2-yl) in tetrahydrofuran (8 mL) ) -7'-hydroxy-11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-[20] oxa [13] thia [1, 14] diazatetracyclo [14.7.2.0 to 3,6 to .0 to 19,24 to] pentacosa [8,16,18,24] tetraene] -15'-on 13 ', 13'-dioxide ( To a solution of 460 mg, 0.641 mmol), sodium hydride (679 mg, 19.24 mmol), a 60% dispersion in mineral oil, was added several times. After addition, the mixture was stirred at room temperature under nitrogen for 10 minutes and then 2-bromoethyl methyl ether (1.809 mL, 19.24 mmol) was added. The resulting mixture was stirred at rt for 14 h. The mixture was quenched with saturated aqueous NH ₄ Cl (150 mL) and extracted twice with EtOAc (200 mL). The combined organic layers were dried over MgSO ₄ and concentrated in vacuo. The residue was purified by chromatography (silica gel; 0% to 100% EtOAc in heptanes) to (1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro- 7 '-(1,3-dithiane-2-yl) -7'-(2-methoxyethoxy) -11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H- Spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6-0.0-19,24-] pentacosa [8,16, 18,24] tetraen] -15'-one 13 ', 13'-dioxide was obtained as a pale yellow solid (391 mg, 0.504 mmol, 79% yield). MS (ESI, Cationic) m / z 699.2, 755.3 (M + H) ⁺ .

Step 2: (1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7 '-(2-methoxyethoxy) -11', 12'-die Methyl-15'-oxo-3,4-dihydro-2H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazettracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] Pentacosa [8,16,18,24] tetraene] -7'-carbaldehyde 13 ', 13'-dioxide

(1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7 '-(1,3-di in acetonitrile (10 mL) and water (2.500 mL) Thian-2-yl) -7 '-(2-methoxyethoxy) -11', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'- [20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraene] -15 To a solution of '-one 13', 13'-dioxide (391 mg, 0.504 mmol) was added iodinemethyl (0.313 mL, 5.04 mmol) and calcium carbonate (252 mg, 2.52 mmol). The resulting mixture was then stirred at 50 ° C. for 14 hours. The mixture was quenched with saturated NH ₄ Cl and extracted twice with EtOAc (100 mL). The combined organic layers were then dried over MgSO ₄ and concentrated in vacuo. The residue was purified by chromatography (silica gel; 0% to 100% EtOAc in heptanes) to (1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro- 7 '-(2-methoxyethoxy) -11', 12'-dimethyl-15'-oxo-3,4-dihydro-2H-spiro [naphthalene-1,22 '-[20] oxa [13 ] Thia [1,14] diaza tetracyclo [14.7.2.0-3,6-0.0-19,24-] pentacosa [8,16,18,24] tetraene] -7'-carbaldehyde 13 ' , 13'-dioxide was obtained as a light yellow solid (233 mg, 0.340 mmol, 67.4% yield). MS (ESI, cation) m / z 685.3 (M + H) ⁺ .

Step 3: 2-methyl-2-propanyl (2R) -2-(((((1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7 '-(2-methoxyethoxy) -11', 12'-dimethyl-13 ', 13'-dioxido-15'-oxo-3,4-dihydro-2H-spiro [naphthalene-1, 22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraene ] -7'-yl) methyl) amino) methyl) -1-piperidinecarboxylate

(1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7 '-(2-methoxyethoxy) -11', 12'-dimethyl-15 '-Oxo-3,4-dihydro-2H-spiro [naphthalene-1,22'-[20] oxa [13] thia [1,14] diazettracyclo [14.7.2.0-3,6-0.0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraene] -7'-carbaldehyde 13 ', 13'-dioxide (55 mg, 0.080 mmol) and 1,2-dichloroethane (0.8 A solution of (R) -tert-butyl 2- (aminoethyl) piperidine-1-carboxylate (172 mg, 0.803 mmol) in mL) was stirred at rt for 14 h. Sodium triacetoxyborohydride (0.059 mL, 0.401 mmol) was added to the mixture, and then the mixture was stirred at room temperature for 1 hour. The mixture was diluted with MeOH (5 mL) and silica gel was added. The mixture was concentrated and dried in vacuo. The solid mixture was then purified by silica gel column chromatography (solid addition; 0% to 100% EtOAc in heptane) to give 2-methyl-2-propanyl (2R) -2-((((((1S, 3 'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-(2-methoxyethoxy) -11 ', 12'-dimethyl-13', 13 '-Dioxido-15'-oxo-3,4-dihydro-2H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0- 3,6 ~ .0 ~ 19,24 ~] Pentacosa [8,16,18,24] tetraen] -7'-yl) methyl) amino) methyl) -1-piperidinecarboxylate light yellow solid Obtained as (64 mg, 0.072 mmol, 90% yield). MS (ESI, cation) m / z 883.5 (M + H) ⁺ .

Step 4: (1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7 '-(2-methoxyethoxy) -11', 12'-die Methyl-7 '-(((((2R) -2-piperidinylmethyl) amino) methyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraen] -15'-one 13 ', 13'-dioxide

2-Methyl-2-propanyl (2R) -2-(((((1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R)-in dichloromethane (0.5 mL)- 6-chloro-7 '-(2-methoxyethoxy) -11', 12'-dimethyl-13 ', 13'-dioxido-15'-oxo-3,4-dihydro-2H-spiro [Naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ 0.19 ~ 24,24] pentacosa [8,16,18 Trifluoroacetic acid (0.098 mL, 1.3 mmol) was added to a solution of, 24] tetraen] -7'-yl) methyl) amino) methyl) -1-piperidinecarboxylate (58 mg, 0.066 mmol). . The resulting mixture was then stirred for 2 hours at room temperature. The mixture was cooled to 0 ° C. and i Pr ₂ Net (0.457 mL, 2.63 mmol) was added followed by 1,2-dibromoethane (0.023 mL, 0.263 mmol) and DMA (0.1 mL). The resulting mixture was then stirred at room temperature for 72 hours and at 50 ° C. for 1 hour. The mixture was concentrated in vacuo and the residue was purified by chromatography (silica gel; 0% to 100% EtOAc in heptanes) to (1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12 ' R) -6-chloro-7 '-(2-methoxyethoxy) -11', 12'-dimethyl-7 '-((((2R) -2-piperidinylmethyl) amino) methyl)- 3,4-Dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6-0.0 19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ', 13'-dioxide was obtained as a colorless oil which was used for the next step. MS (ESI, cation) m / z 783.3 (M + H) ⁺ .

Step 5: (1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7 '-(2-methoxyethoxy) -11', 12'-die Methyl-7 '-((9aR) -octahydro-2H-pyrido [1,2-a] pyrazin-2-ylmethyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1 , 22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetra EN] -15'-one 13 ', 13'-dioxide

In (1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7 '-(2-methoxy- in N, N-dimethylacetamide (0.4 mL) Methoxy) -11 ', 12'-dimethyl-7'-(((((2R) -2-piperidinylmethyl) amino) methyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene -1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6-0.0-19,24-] pentacosa [8,16,18,24 ] Tetraen] -15'-one 13 ', 13'-dioxide (51.4 mg, 0.066 mmol) in a solution of i Pr ₂ Net (0.057 mL, 0.328 mmol) and 1,2-dibromoethane (0.028 mL, 0.328 mmol) was added. The resulting mixture was then stirred at rt for 14 h. Then 1,2-dibromoethane (0.2 mL) was added and the mixture was stirred at room temperature for 14 hours and then at 55 ° C. for 72 hours. The mixture was purified by silica gel column chromatography (0% to 10% MeOH in DCM) (1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7 ' -(2-methoxyethoxy) -11 ', 12'-dimethyl-7'-((9aR) -octahydro-2H-pyrido [1,2-a] pyrazin-2-ylmethyl) -3 , 4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diaza tetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ', 13'-dioxide was obtained as a light yellow solid (17 mg, 0.021 mmol, 32.0% yield). MS (ESI, cation) m / z 809.2 (M + H) ⁺ .

Example 154

(1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-methoxy-11 ', 12'-dimethyl-7'-(( (9aR) -3-oxooctahydro-2H-pyrido [1,2-a] pyrazin-2-yl) methyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraene -15'-on 13 ', 13'-dioxide

Step 1: 2-methyl-2-propanyl (2R) -2-(((((1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro -7'-methoxy-11 ', 12'-dimethyl-13', 13'-dioxido-15'-oxo-3,4-dihydro-2H-spiro [naphthalene-1,22 '-[ 20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraen] -7 ' -Yl) methyl) amino) methyl) -1-piperidinecarboxylate

(1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-methoxy-11 'in 1,2-dichloroethane (1 mL) , 12'-dimethyl-15'-oxo-3,4-dihydro-2H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7. 2.0-3,6 ~ .0 ~ 19,24 ~] Pentacosa [8,16,18,24] tetraene] -7'-carbaldehyde 13 ', 13'-dioxide (44 mg, 0.069 mmol) To (R) -tert-butyl 2- (aminomethyl) piperidine-1-carboxylate (147 mg, 0.686 mmol) was added. The resulting mixture was then stirred for 1 hour at room temperature. Then sodium triacetoxyborohydride (73 mg, 0.343 mmol) was added several times. After addition, the mixture was stirred for 3 days at room temperature. The mixture was purified by silica gel column chromatography (0% to 20% MeOH in DCM) to afford 2-methyl-2-propanyl (2R) -2-(((((1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-Chloro-7'-methoxy-11 ', 12'-dimethyl-13', 13'-deoxido-15'-oxo-3 , 4-dihydro-2H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~ ] Pentacosa [8,16,18,24] tetraen] -7'-yl) methyl) amino) methyl) -1-piperidinecarboxylate was obtained as a light yellow solid (57.6 mg, 0.069 mmol, 100 % Yield), used in these next steps. MS (ESI, cation) m / z 839.4 (M + H) ⁺ .

Step 2: 2-methyl-2-propanyl (2R) -2-(((chloroacetyl) (((1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-methoxy-11 ', 12'-dimethyl-13', 13'-dioxido-15'-oxo-3,4-dihydro-2H-spiro [naphthalene-1, 22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraene ] -7'-yl) methyl) amino) methyl) -1-piperidinecarboxylate

2-Methyl-2-propanyl (2R) -2-(((((1S, 3'R, 6'R, 7'R, 8'E) in dichloromethane (1.5 mL) at -78 ° C under nitrogen. , 11'S, 12'R) -6-Chloro-7'-methoxy-11 ', 12'-dimethyl-13', 13'-dioxido-15'-oxo-3,4-dihydro-2H Spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6-0.0-19,24-] pentacosa [8,16 To a solution of 18,24] tetraen] -7'-yl) methyl) amino) methyl) -1-piperidinecarboxylate (57.6 mg, 0.069 mmol) was added chloroacetyl chloride (10.92 μL, 0.137 mmol). Then i Pr ₂ Net (0.036 mL, 0.206 mmol) was added. After addition, the mixture was stirred at -78 ° C for 1.5 h. Chloroacetyl chloride (0.022 mL) was added and the mixture was stirred at -25 ° C for 1 hour and left in a freezer at -20 ° C for 16 hours. The mixture was quenched with MeOH (2 mL) and concentrated in vacuo. 2-methyl-2-propanyl (2R) -2-(((chloroacetyl) (((1S, 3'R, 6 ') via chromatography purification (silica gel; 0% to 100% EtOAc in heptane) R, 7'R, 8'E, 11'S, 12'R) -6-Chloro-7'-methoxy-11 ', 12'-dimethyl-13', 13'-dioxido-15'-oxo -3,4-dihydro-2H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diaza tetracyclo [14.7.2.0-3,6-0.0-19, 24 ~] pentacosa [8,16,18,24] tetraen] -7'-yl) methyl) amino) methyl) -1-piperidinecarboxylate was obtained as a light yellow solid (62.8 mg, 0.069 mmol , 100% yield). MS (ESI, Cation) m / z 937.3, 939.2 (M + Na) ⁺ .

Step 3: (1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-methoxy-11 ', 12'-dimethyl-7' -(((9aR) -3-oxooctahydro-2H-pyrido [1,2-a] pyrazin-2-yl) methyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene- 1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] Tetraene] -15'-one 13 ', 13'-dioxide

2-methyl-2-propanyl (2R) -2-(((chloroacetyl) (((1S, 3'R, 6'R, 7'R, 8'E, 11'S) in dichloromethane (1 mL) , 12'R) -6-Chloro-7'-methoxy-11 ', 12'-dimethyl-13', 13'-dioxido-15'-oxo-3,4-dihydro-2H-spiro [Naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ 0.19 ~ 24,24] pentacosa [8,16,18 To a solution of, 24] tetraen] -7'-yl) methyl) amino) methyl) -1-piperidinecarboxylate (61.8 mg, 0.067 mmol) was added trifluoroacetic acid (0.251 mL, 3.37 mmol). After addition, the mixture was stirred at room temperature for 17 minutes. The mixture was cooled to -78 ° C and i PrNEt (0.704 mL, 4.05 mmol) was added dropwise. After addition, the mixture was stirred at rt for 14 h. The mixture was purified by silica gel chromatography (0% to 20% MeOH in DCM), then preparative HPLC (Phenomenex Gemini C18 column, 150 × 30 mm, 10% to 100% MeCN in H ₂ O (0.1% TFA) Containing) to afford the desired product as a solution of MeCN / H ₂ O (containing 0.1% TFA). The pH was adjusted to 7 with buffer (KH ₂ PO ₄ / K ₂ HPO ₄ ) and extracted twice with EtOAc (10 mL). The combined extracts were washed with brine, dried (Na ₂ SO ₄ ), concentrated and dried in vacuo (1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R)- 6-chloro-7'-methoxy-11 ', 12'-dimethyl-7'-(((9aR) -3-oxooctahydro-2H-pyrido [1,2-a] pyrazin-2-yl ) Methyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diaza tetracyclo [14.7.2.0-3, 6 ~ .0 ~ 19,24 ~] Pentacosa [8,16,18,24] tetraen] -15'-one 13 ', 13'-dioxide was obtained as an off-white solid (33 mg, 0.042 mmol, 62.8 % Yield). MS (ESI, cation) m / z 779.3 (M + H) ⁺ .

Examples 176 and 177

(1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-methoxy-N, N, 11 ', 12'-tetramethyl-15'- Oxo-3,4-dihydro-2H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazettracyclo [14.7.2.0-3,6-0.0-19 , 24 ~] pentacosa [8,16,18,24] tetraene] -7'-carboxamide 13 ', 13'-dioxide and (1S, 3'R, 6'R, 7'R, 8' E, 11'S, 12'R) -6-Chloro-7'-methoxy-N, N, 11 ', 12'-tetramethyl-15'-oxo-3,4-dihydro-2H-spiro [naphthalene- 1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] Tetraene] -7'-carboxamide 13 ', 13'-dioxide

Step 1: (1S, 3'R, 6'R, 8'E, 11'S, 12'R) -6-Chloro-11 ', 12'-dimethyl-15'-oxo-7'-methoxy-3 , 4-dihydro-2H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~ ] Pentacosa [8,16,18,24] tetraene] -7'-carboxylic acid 13 ', 13'-dioxide

In a 15 mL round-bottom flask (1S, 3'R, 6'R, 8'E, 11'S, 12'R) -6-chloro-11 ', in tert-butanol (281 μL) and water (281 μL), 12'-dimethyl-15'-oxo-7'-methoxy-3,4-dihydro-2H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diaza Tetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraene] -7'-carbaldehyde 13 ', 13'-dioxide (18 mg , 0.028 mmol, a mixture of two epimers) and 2-methyl-2-butene (149 μL, 1.404 mmol) were added. Monobasic potassium phosphate (38.2 mg, 0.281 mmol) and sodium chloride (25.4 mg, 0.281 mmol) were added to the solution. The solution was stirred at rt for 1 h. The reaction mixture was diluted with saturated Na ₂ SO ₃ (5 mL) and extracted three times with DCM (10 mL). The organic extract was washed with saturated NaCl (10 mL) and dried over MgSO ₄ . The solution was filtered and concentrated in vacuo to yield an off-white solid. The material was used for the next step without further purification. MS (ESI, cation) m / z 657.2 (M + H) ⁺ .

Step 2: (1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-methoxy-N, N, 11 ', 12'-tetramethyl- 15'-oxo-3,4-dihydro-2H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diaza tetracyclo [14.7.2.0-3,6]. 0-19,24-] pentacosa [8,16,18,24] tetraene] -7'-carboxamide 13 ', 13'-dioxide and (1S, 3'R, 6'R, 7'R , 8'E, 11'S, 12'R) -6-chloro-7'-methoxy-N, N, 11 ', 12'-tetramethyl-15'-oxo-3,4-dihydro-2H-spiro [Naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ 0.19 ~ 24,24] pentacosa [8,16,18 , 24] tetraene] -7'-carboxamide 13 ', 13'-dioxide

In a 5 mL round bottom flask (1S, 3'R, 6'R, 8'E, 11'S, 12'R) -6-chloro-11 ', 12'-dimethyl-15'-oxo-7'- Methoxy-3,4-dihydro-2H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diaza tetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraene] -7'-carboxylic acid 13 ', 13'-dioxide (13 mg, 0.020 mmol, mixture of two epimers) and DCM (396 μL) Diethylamine (2M in THF, 39.6 μL, 0.079 mmol) was added. 1-propanephosphonic acid cyclic anhydride (50 wt% solution in ethyl acetate, 62.9 μL, 0.099 mmol) was added at room temperature. The solution was stirred at rt for 2 h. The reaction mixture was diluted with saturated NaHCO ₃ (5 mL) and extracted twice with EtOAc (10 mL). The organic layer was concentrated. The crude was further purified by prep-HPLC to give two products. The collected first peak was assigned to Example 176 and the second peak was assigned to Example 177. MS (ESI, cation) m / z 684.2 (M + H) ⁺ for both isomers.

Examples 193 and 213

(1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7 '-((9aS) -hexahydropyrazino [2,1-c] [1, 4] oxazine-8 (1H) -ylmethyl) -7'-hydroxy-11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22' [20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraene]- 15'-one 13 ', 13'-dioxide and (1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-((9aS)- Hexahydropyrazino [2,1-c] [1,4] oxazine-8 (1H) -ylmethyl) -7'-hydroxy-11 ', 12'-dimethyl-3,4-dihydro- 2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] penta Cosa [8,16,18,24] tetraene] -15'-on 13 ', 13'-dioxide

Step 1: (1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-7 '-(hydroxymethyl) -11', 12 '-Dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-[20] oxa [13] thia [1,14] diaza tetracyclo [14.7.2.0-3] , 6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraene] -15'-one 13 ', 13'-dioxide and (1S, 3'R, 6'R, 7 'R, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-7'-(hydroxymethyl) -11 ', 12'-dimethyl-3,4-dihydro-2H , 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6-0.0-19,24-] pentacosa [8,16,18,24] tetraene] -15'-on 13 ', 13'-dioxide

(1S, 3'R, 6'R, 8'E, 11'S, 12'R) -6-chloro-11 ', 12'-dimethyl-3,4-dihydro in dimethyl sulfoxide (4.0 mL) -2H, 7'H, 15'H-spiro [naphthalene-1,22 '[20] oxa [13] thia [1,14] diazettracyclo [14.7.2.0-3,6 ~ .0 ~ 19, 24 ~] pentacosa [8,16,18,24] tetraene] -7 ', 15'-dione 13', 13'-dioxide (1.015 g, 1.700 mmol) and trimethylsulfonium iodide (0.364 g, 1.785 mmol) was stirred and ice-cooled was added potassium tert-butoxide (4.25 mL, 4.25 mmol), 1.0 M solution in tetrahydrofuran, under argon. The resulting mixture was stirred for 5 minutes in an ice bath and for 30 minutes at ambient temperature. The crude reaction mixture was added directly onto a silica gel precolumn (25 g) pre-coated with an ammonium chloride layer, eluted with 24 g of ISCO gold column (0% to 100% EtOAc in hexanes, then 5% to DCM). Eluting with 20% MeOH) (1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-hydride by separation with combi-flash column chromatography Hydroxy-7 '-(hydroxymethyl) -11', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diaza tetracyclo [14.7.2.0-3,6-0.0-19,24-] pentacosa [8,16,18,24] tetraene] -15'-one 13 ', 13' -Dioxide and (1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-7 '-(hydroxymethyl) -11' , 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0 ~ 3,6 ~ .0 ~ 19,24 ~] Pentacosa [8,16,18,24] tetraene] -15'-one 13 ', 13'-dioxide (approximately 3: 1 ratio) It was obtained as a color solid (0.82 g, 1.3 mmol, 79% yield). MS (ESI, cation) m / z 629.2 (M + l) ⁺ .

Step 2: (1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-11 ', 12'-dimethyl-15'-oxo -3,4-dihydro-2H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diaza tetracyclo [14.7.2.0-3,6-0.0-19, 24 ~] pentacosa [8,16,18,24] tetraene] -7'-carbaldehyde 13 ', 13'-dioxide and (1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-Chloro-7'-hydroxy-11 ', 12'-dimethyl-15'-oxo-3,4-dihydro-2H-spiro [naphthalene-1,22'-[ 20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraen] -7 ' Carbaldehyde 13 ', 13'-dioxide

(1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-7 '-(hydroxymethyl) -11 in DCM (5.0 mL) ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-[20] oxa [13] thia [1,14] diazatetracyclo [14.7. 2.0 ~ 3,6 ~ .0 ~ 19,24 ~] Pentacosa [8,16,18,24] tetraene] -15'-one 13 ', 13'-dioxide and (1S, 3'R, 6' R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-7 '-(hydroxymethyl) -11', 12'-dimethyl-3,4-di Hydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~ ] Des-Martin as a solid in a solution of pentacosa [8,16,18,24] tetraen] -15'-on 13 ', 13'-dioxide (180 mg, 0.286 mmol), cooled with ice and cooled Periodinan (121 mg, 0.286 mmol) was added in one portion under argon. The resulting mixture was stirred at 0 ° C. for 10 minutes under argon and for 3 hours at ambient temperature. The crude mixture was added directly onto silica gel precolumn (25 g) and separated by combi-flash column chromatography using 12 g ISCO gold column (eluted with 0% to 20% MeOH in DCM) ( 1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-11 ', 12'-dimethyl-15'-oxo-3,4 Dihydro-2H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6-0.0-19,24-] penta Cosa [8,16,18,24] tetraene] -7'-carbaldehyde 13 ', 13'-dioxide and (1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12' R) -6-chloro-7'-hydroxy-11 ', 12'-dimethyl-15'-oxo-3,4-dihydro-2H-spiro [naphthalene-1,22'-[20] oxa [ 13] thia [1,14] diazettracyclo [14.7.2.0-3,6-0.0-19,24-] pentacosa [8,16,18,24] tetraene] -7'-carbaldehyde 13 180 mg of an unpurified mixture of ', 13'-dioxide was obtained as an off-white solid. It was used for the next step without further purification. MS (ESI, cation) m / z 627.2 (M + l) ⁺ .

Step 3: (1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7 '-((9aS) -hexahydropyrazino [2,1-c] [1,4] oxazine-8 (1H) -ylmethyl) -7'-hydroxy-11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1 , 22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetra N] -15'-one 13 ', 13'-dioxide and (1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-(( 9aS) -hexahydropyrazino [2,1-c] [1,4] oxazine-8 (1H) -ylmethyl) -7'-hydroxy-11 ', 12'-dimethyl-3,4- Dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazettracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 Pentacosa [8,16,18,24] tetraene] -15'-on 13 ', 13'-dioxide

(1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-11 ', 12'-dimethyl-15' according to general method 10 Oxo-3,4-dihydro-2H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diaza tetracyclo [14.7.2.0-3,6-0.0 ... 19,24 ~] pentacosa [8,16,18,24] tetraene] -7'-carbaldehyde 13 ', 13'-dioxide and (1S, 3'R, 6'R, 7'R, 8' E, 11'S, 12'R) -6-Chloro-7'-hydroxy-11 ', 12'-dimethyl-15'-oxo-3,4-dihydro-2H-spiro [naphthalene-1,22' [20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraene]- The title compounds were prepared from a mixture of 7'-carbaldehyde 13 ', 13'-dioxide. (1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7 '-((9aS) -hexahydropyrazino [2,1-c] [1, 4] oxazine-8 (1H) -ylmethyl) -7'-hydroxy-11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22' [20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraene]- 15'-on 13 ', 13'-dioxide (Example 193) was the second eluting epimer in a silica gel column. MS (ESI, cation) m / z 753.3 (M + l) ⁺ . (1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7 '-((9aS) -hexahydropyrazino [2,1-c] [ 1,4] oxazine-8 (1H) -ylmethyl) -7'-hydroxy-11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1, 22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraene ] -15'-on 13 ', 13'-dioxide (Example 213) was the first eluting epimer in a silica gel column. MS (ESI, cation) m / z 753.3 (M + l) ⁺ .

Example 194

(1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-11 ', 12'-dimethyl-7'-(4-mo Polyylmethyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diaza tetracyclo [14.7.2.0-3] , 6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraene] -15'-on 13 ', 13'-dioxide

Step 1: (1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-7 '-(hydroxymethyl) -11', 12 '-Dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-[20] oxa [13] thia [1,14] diaza tetracyclo [14.7.2.0-3] , 6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraene] -15'-on 13 ', 13'-dioxide

The title compound is (1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-7 '-(hydroxymethyl) -11', 12 '-Dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-[20] oxa [13] thia [1,14] diaza tetracyclo [14.7.2.0-3] , 6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraene] -15'-one 13 ', 13'-dioxide and (1S, 3'R, 6'R, 7 'R, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-7'-(hydroxymethyl) -11 ', 12'-dimethyl-3,4-dihydro-2H , 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6-0.0-19,24-] pentacosa The epimeric mixture of [8,16,18,24] tetraen] -15'-on 13 ', 13'-dioxide was subjected to a single silica gel column chromatography separation eluting with 1% to 20% MeOH in DCM. Obtained as stereoisomer. The title compound was the second eluting epimer on a silica gel column. MS (ESI, cation) m / z 629.3 (M + l) ⁺ .

Step 2: (1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-11 ', 12'-dimethyl-15'-oxo -3,4-dihydro-2H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diaza tetracyclo [14.7.2.0-3,6-0.0-19, 24 ~] pentacosa [8,16,18,24] tetraene] -7'-carbaldehyde 13 ', 13'-dioxide

The title compound was prepared according to the protocol in Example 193 (step 2) ((1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy- 7 '-(hydroxymethyl) -11', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1 , 14] diaza tetracyclo [14.7.2.0-3,6-0.0-19,24-] pentacosa [8,16,18,24] tetraene] -15'-one 13 ', 13'-dioxide MS (ESI, cation) m / z 627.4 (M + l) ⁺ .

Step 3: (1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-11 ', 12'-dimethyl-7'-( 4-morpholinylmethyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7. 2.0 ~ 3,6 ~ .0 ~ 19,24 ~] Pentacosa [8,16,18,24] tetraene] -15'-on 13 ', 13'-dioxide

The title compound is prepared according to general method 10 (1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-11 ', 12'-dimethyl -15'-oxo-3,4-dihydro-2H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diaza tetracyclo [14.7.2.0-3,6] .0 to 19,24 to] pentacosa [8,16,18,24] tetraene] -7'-carbaldehyde 13 ', 13'-dioxide. MS (ESI, cation) m / z 698.5 (M + l) ⁺ .

Example 270

(4-(((1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-methoxy-11 ', 12'-dimethyl-13' , 13'-dioxido-15'-oxo-3,4-dihydro-2H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazettracyclo [14.7 .2.0 ~ 3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraen] -7'-yl) methyl) -1-piperazinyl) acetic acid

Methyl (4-(((1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-meth) in MeOH (1.5 mL) and water (0.5 mL) Toxy-11 ', 12'-dimethyl-13', 13'-dioxido-15'-oxo-3,4-dihydro-2H-spiro [naphthalene-1,22 '-[20] oxa [13 ] Thia [1,14] diaza tetracyclo [14.7.2.0-3,6-0.0-19,24-] pentacosa [8,16,18,24] tetraen] -7'-yl) methyl) Lithium hydroxide hydrate (8.0 mg, 0.19 mmol) was added to a stirred solution of -1-piperazinyl) acetate (Example 269) (15 mg, 0.019 mmol). The resulting mixture was stirred at rt for 3 h. The residue was dissolved in MeOH and preparative reversed phase HPLC (Gemini ™ Prep C18 10 μm column; Phenomenex, Torrance, CA; eluted with 20% to 90% gradient of MeCN in water, with both solvents using 0.1% TFA Separated by a 15 minute gradient in a 24 minute method, followed by freeze-drying, and 11 mg (4-(((1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R)) -6-chloro-7'-methoxy-11 ', 12'-dimethyl-13', 13'-dioxido-15'-oxo-3,4-dihydro-2H-spiro [naphthalene-1, 22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraene ] -7'-yl) methyl) -1-piperazinyl) acetic acid was obtained as a white solid. MS (ESI, cation) m / z 769.7 (M + l) ⁺ .

Example 276

(1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -7 '-(((9aS) -8-acryloyloctahydro-2H-pyrazino [1,2- a] pyrazin-2-yl) methyl) -6-chloro-7'-methoxy-11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraene -15'-one 13 ', 13'-dioxide or (1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -7'-(((9aR) -8-acrylo Octahydro-2H-pyrazino [1,2-a] pyrazin-2-yl) methyl) -6-chloro-7'-methoxy-11 ', 12'-dimethyl-3,4-dihydro- 2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] penta Cosa [8,16,18,24] tetraene] -15'-on 13 ', 13'-dioxide

(1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-methoxy-11 ', 12 in pyridine (0.30 mL) in a microwave reaction vessel '-Dimethyl-7'-(((9aS) -8- (3- (phenylsulfonyl) propanoyl) octahydro-2H-pyrazino [1,2-a] pyrazin-2-yl) methyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6]. 0-19,24-] pentacosa [8,16,18,24] tetraene] -15'-on 13 ', 13'-dioxide solution or (1S, 3'R, 6'R, 7'S, 8' E, 11'S, 12'R) -6-Chloro-7'-methoxy-11 ', 12'-dimethyl-7'-(((9aR) -8- (3- (phenylsulfonyl) propanoyl ) Octahydro-2H-pyrazino [1,2-a] pyrazin-2-yl) methyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraen] -15'-one 13 In a solution of ', 13'-dioxide (15 mg, 0.016 mmol) and 1,8-diazabicyclo- [5.4.0] undec-7-ene (0.15 mL, 1.0 mmol) at 75 ° C. The microwave was irradiated for 50 minutes. The crude mixture was dissolved in MeOH and preparative reversed phase HPLC (Gemini ™ Prep C ₁₈ 10 μm column; Phenomenex, Torrance, CA; eluted with 20% to 90% gradient MeCN in water, with both solvents 0.1% TFA 7.5 mg (1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -7'- (((9aS) -8-acryloyloctahydro-2H-pyrazino [1,2-a] pyrazin-2-yl) methyl) -6-chloro-7'-methoxy-11 ', 12'- Dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazettracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] Pentacosa [8,16,18,24] tetraene] -15'-one 13 ', 13'-dioxide or (1S, 3'R, 6'R, 7'S, 8 'E, 11'S, 12'R) -7'-(((9aR) -8-acryloyloctahydro-2H-pyrazino [1,2-a] pyrazin-2-yl) methyl) -6-chloro -7'-methoxy-11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-[20] oxa [13] thia [1,14 Diazatetracycle [14.7.2.0 ~ 3,6 ~ .0 ~ 19,24 ~] penta Kosa [8,16,18,24] tetraene] was obtained -15'- on 13 ', 13'- dioxide. MS (ESI, cation) m / z 821.0 (M + l) ⁺ .

Example 345

(1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-methoxy-11 ', 12'-dimethyl-7'-(1H -1,2,3-triazol-1-ylmethyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14 ] Diazatetracyclo [14.7.2.0-3,6-0.0-19,24-] pentacosa [8,16,18,24] tetraene] -15'-one 13 ', 13'-dioxide or ( 1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-methoxy-11 ', 12'-dimethyl-7'-(1H-1, 2,3-triazol-1-ylmethyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diaza Tetracyclo [14.7.2.0 ~ 3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraene] -15'-one 13 ', 13'-dioxide

Step 1: (1S, 3'R, 6'R, 8'E, 11'S, 12'R) -6-chloro-11 ', 12'-dimethyl-7'-methylidene-3,4-dihydro -2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] Pentacosa [8,16,18,24] tetraene] -15'-on 13 ', 13'-dioxide

A solution of methyltriphenylphosphonium bromide (1.80 g, 5.0 mmol) in THF (15 mL) was cooled to 0 ° C. n-butyllithium solution (2.5 M in hexane, 1.8 mL, 4.5 mmol) was added dropwise and stirred at 0 ° C. for 10 min. (1S, 3'R, 6'R, 8'E, 11'S, 12'R) -6-chloro-11 ', 12'-dimethyl-3, in THF (6.0 mL) (cooled in ice bath) 4-dihydro-2H, 7'H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diaza tetracyclo [14.7.2.0-3,6] .0 ~ 19,24 ~] Pentacosa [8,16,18,24] tetraene] -7 ', 15'-dione 13', 13'-dioxide (0.30 g, 0.50 mmol) solution remains yellow The bromide solution was added dropwise until this solution. It was stirred at 0 ° C. for 12 minutes. The reaction mixture was added to stirred ice water (20 mL). It was acidified with 1 N HCl to pH 2-4. The organic phase was separated and the aqueous phase was extracted with EtOAc (50 mL). The organic phase was washed with brine and dried over magnesium sulfate. The filtrate was concentrated to give crude product. The compound was purified by medium pressure chromatography (silica; 0% to 50% EtOAc in hexanes containing 0.3% HOAc) (1S, 3'R, 6'R, 8'E, 11'S, 12'R) -6- Chloro-11 ', 12'-dimethyl-7'-methylidene-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-[20] oxa [13] thia [1, 14] diazatetracyclo [14.7.2.0 to 3,6 to .0 to 19,24 to] pentacosa [8,16,18,24] tetraene] -15'-on 13 ', 13'-dioxide Obtained (290 mg, 0.49 mmol, 97% yield). MS (ESI, cation) m / z 595.2 (M + H) ⁺ .

Step 2: (1S, 3'R, 6'R, 8'E, 11'S, 12'R) -6-Chloro-7'-hydroxy-7 '-(hydroxymethyl) -11', 12'- Dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazettracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] Pentacosa [8,16,18,24] tetraene] -15'-one 13 ', 13'-dioxide

The AD-Mix-alpha mixture (640 mg, 0.43 mmol) was dissolved in 20 mL of a 1: 1 mixture of tert-butanol (10.0 mL) and water (10.0 mL) and cooled to 0 ° C. (1S, 3'R, 6'R, 8'E, 11'S, 12'R) -6-Chloro-11 ', 12'-dimethyl-7'-methylidene-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6-0.0-19,24-] pentacosa [ 8,16,18,24] tetraen] -15'-one 13 ', 13'-dioxide (255 mg, 0.428 mmol) was added and the reaction mixture was allowed to slowly warm up to room temperature overnight. An additional 5.0 mL of t-BuOH was added to homogenize the mixture. The reaction was stirred overnight. An additional 320 mg of AD-Mix-alpha mixture was added and the reaction was further stirred for 3 days. 575 mg of sodium sulfite was added at 0 ° C. and stirred at 0 ° C. for 45 minutes to quench the reaction. The mixture was then extracted twice with EtOAc (25 mL). The combined organic layers were washed with brine (1 x 20 mL) and dried over sodium sulfate. The crude product is then purified by medium pressure chromatography (silica; 0% to 100% EtOAc in heptane with + 0.3% HOAc) (1S, 3'R, 6'R, 8'E, 11'S, 12). 'R) -6-chloro-7'-hydroxy-7'-(hydroxymethyl) -11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1 , 22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetra En] -15'-one 13 ', 13'-dioxide was obtained (31 mg, 0.049 mmol, 12% yield). MS (ESI, cation) m / z 629.2 (M + H) ⁺ .

Step 3: ((1S, 3'R, 6'R, 8'E, 11'S, 12'R) -6-Chloro-7'-hydroxy-11 ', 12'-dimethyl-13', 13 ' -Dioxido-15'-oxo-3,4-dihydro-2H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0- 3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraen] -7'-yl) methyl methanesulfonate

(1S, 3'R, 6'R, 8'E, 11'S, 12'R) -6-Chloro-7'-hydroxy-7 '-(hydroxymethyl) -11', 12'-dimethyl- 3,4-Dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diaza tetracyclo [14.7.2.0-3,6-0.0] ~ 19,24 ~] pentacosa [8,16,18,24] tetraen] -15'-one 13 ', 13'-dioxide (25.0 mg, 0.040 mmol) is dissolved in DCM (800 μL) and 0 ° C. Cooled to. Triethylamine (17 μL, 0.12 mmol) was added followed by mesyl chloride (6.50 μL, 0.083 mmol) and the reaction stirred for 1.5 h. The reaction was then diluted with DCM (15 mL) and the mixture was washed twice with water (10 mL) and dried over sodium sulfate. The crude product was then purified by medium pressure chromatography (silica; 0% to 70% EtOAc in heptane with + 0.3% HOAc) ((1S, 3'R, 6'R, 8'E, 11'S, 12). 'R) -6-chloro-7'-hydroxy-11', 12'-dimethyl-13 ', 13'-dioxido-15'-oxo-3,4-dihydro-2H-spiro [naphthalene -1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24 ] Tetraen] -7'-yl) methyl methanesulfonate was obtained. MS (ESI, cation) m / z 707.2 (M + H) ⁺ .

Step 4: (1S, 3'R, 6'R, 8'E, 11'S, 12'R) -7 '-(azidomethyl) -6-chloro-7'-hydroxy-11', 12'- Dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazettracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] Pentacosa [8,16,18,24] tetraene] -15'-one 13 ', 13'-dioxide

((1S, 3'R, 6'R, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-11 ', 12'-dimethyl-13', 13'-dioxy Fig. 15'-Oxo-3,4-dihydro-2H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] Pentacosa [8,16,18,24] tetraen] -7'-yl) methyl methanesulfonate (10 mg, 0.014 mmol) in a 5: 1 ratio of DMF: water mixture Dissolved in 0.36 mL. To the solution was added sodium azide (2.1 mg, 3.2 μmol). The mixture was heated to 70 ° C. and stirred overnight. The reaction was diluted with water and extracted with EtOAc. The organic layer was dried over sodium sulfate and the crude product was purified by medium pressure chromatography (silica; 0% to 60% EtOAc in heptane (containing 0.3% HOAc)) (1S, 3'R, 6'R, 8'E). , 11'S, 12'R) -7 '-(azidomethyl) -6-chloro-7'-hydroxy-11', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [Naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18 , 24] tetraen] -15'-one 13 ', 13'-dioxide was obtained (2.1 mg, 3.2 μmol, 23% yield). MS (ESI, cation) m / z 654.2 (M + H) ⁺ .

Step 5: (1S, 3'R, 6'R, 8'E, 11'S, 12'R) -7 '-(azidomethyl) -6-chloro-7'-methoxy-11', 12'- Dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazettracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] Pentacosa [8,16,18,24] tetraene] -15'-one 13 ', 13'-dioxide

(1S, 3'R, 6'R, 8'E, 11'S, 12'R) -7 '-(azidomethyl) -6-chloro-7'-hydroxy-11', 12'-dimethyl- 3,4-Dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6-0.0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraene] -15'-on 13 ', 13'-dioxide (2.0 mg, 3.1 μmol) 2-methyltetrahydrofuran (1.0 mL) Sodium hydride (60% dispersion) (0.73 mg, 0.031 mmol) was added followed by methyl iodide (0.956 μL, 0.015 mmol). The reaction was then stirred overnight to complete the reaction. The reaction was quenched by the dropwise addition of water and extracted with EtOAc. The organic layer was then washed with brine and dried over magnesium sulfate (1S, 3'R, 6'R, 8'E, 11'S, 12'R) -7 '-(azidomethyl) -6-chloro-7 '-Methoxy-11', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] dia Zatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] Pentacosa [8,16,18,24] tetraene] -15'-one 13 ', 13'-dioxide (3.0 mg) Was obtained and used directly in the next reaction without any further purification. MS (ESI, cation) m / z 668.2 (M + H) ⁺ .

Step 6: (1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-methoxy-11 ', 12'-dimethyl-7' -(1H-1,2,3-triazol-1-ylmethyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [ 1,14] diatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraene] -15'-one 13 ', 13'- Dioxide or (1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-methoxy-11 ', 12'-dimethyl-7'-(1H -1,2,3-triazol-1-ylmethyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14 ] Diazatetracyclo [14.7.2.0 ~ 3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraene] -15'-one 13 ', 13'-dioxide

(1S, 3'R, 6'R, 8'E, 11'S, 12'R) -7 '-(azidomethyl) -6-chloro-7'-methoxy-11', 12'-dimethyl- 3,4-Dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6-0.0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraene] -15'-one 13 ', 13'-dioxide (20 mg, 0.030 mmol) in a 1: 1: 1 ratio of t-BuOH Slurried in a water: DMF solution. To the solution was added copper (II) sulfate (2.9 mg, 0.018 mmol), ( + )-L-sodium ascorbate (12.0 mg, 0.061 mmol) and (trimethyl) acetylene (65 μL, 0.46 mmol). The solution was then heated in a microwave reactor at 120 ° C. for 2 hours. The reaction was then diluted with water and EtOAc. The mixture was extracted twice with EtOAc (25 mL). The combined organic layers were washed with 1 N lithium chloride solution (1 x 15 mL) and brine (1 x 15 mL) and then dried over magnesium sulfate. The residue was then purified by medium pressure chromatography (silica; 25% to 100% EtOAc in heptane (containing 0.3% HOAc)) (1S, 3'R, 6'R, 7'R, 8'E). , 11'S, 12'R) -6-chloro-7'-methoxy-11 ', 12'-dimethyl-7'-(1H-1,2,3-triazol-1-ylmethyl) -3, 4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19 , 24 ~] pentacosa [8,16,18,24] tetraen] -15'-one 13 ', 13'-dioxide or (1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-methoxy-11 ', 12'-dimethyl-7'-(1H-1,2,3-triazol-1-ylmethyl) -3,4-di Hydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~ ] Pentacosa [8,16,18,24] tetraen] -15'-one 13 ', 13'-dioxide was obtained. MS (ESI, cation) m / z 694.3 (M + H) ⁺ .

Example 348

(1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-11 ', 12'-dimethyl-7'-(2-methoxylpropoxy) -7 '-((4- (3-oxetanyl) -1-piperazinyl) methyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-[20] oxa [ 13] thia [1,14] diatetracyclo [14.7.2.0-3,6-0.0-19,24-] pentacosa [8,16,18,24] tetraene] -15'-one 13 ' , 13'-dioxide

Step 1: (1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7 '-(1,3-dithia-2--2-)-11', 12'-dimethyl-7 '-((2-methyl-2-propen-1-yl) oxy) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-[ 20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraen] -15 ' -On 13 ', 13'-dioxide

The reaction was carried out according to the procedure for step 2 of general method 5. MS (ESI, cation) m / z 771.2 (M + H) ⁺ .

Step 2: (1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7 '-(1,3-ditian-2-yl) -11', 12'-dimethyl-7 '-(2-methoxylpropoxy) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-[20] oxa [13] thia [1 , 14] diaza tetracyclo [14.7.2.0-3,6-0.0-19,24-] pentacosa [8,16,18,24] tetraene] -15'-one 13 ', 13'-dioxide

(1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7 '-(1,3-dithiane-2-yl) -11', 12'- Dimethyl-7 '-((2-methyl-2-propen-1-yl) oxy) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraen] -15'-one 13 ', 13'-dioxide (200 mg, 0.26 mmol) was dissolved in EtOAc (5.0 mL) and platinum (IV) oxide (180 mg, 0.78 mmol) was added. The vessel was then pressurized with hydrogen to 40 psi and stirred for 3.5 hours to complete the reaction. The black slurry was then filtered through a pad of celite and washed with EtOAc. The filtrate was then concentrated to (1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7 '-(1,3-dithiane-2-yl) -11 ', 12'-dimethyl-7'-(2-methoxylpropoxy) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13 ] Thia [1,14] diaza tetracyclo [14.7.2.0-3,6-0.0-19,24-] pentacosa [8,16,18,24] tetraene] -15'-one 13 ', 13'-dioxide was obtained (200 mg, 0.26 mmol, 100% yield). MS (ESI, cation) m / z 773.2 (M + H) ⁺ .

Step 3: (1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-11 ', 12'-dimethyl-7'-(2-methoxylpropoxy ) -15'-oxo-3,4-dihydro-2H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazettracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] Pentacosa [8,16,18,24] tetraene] -7'-carbaldehyde 13 ', 13'-dioxide

The reaction was carried out according to the procedure for step 3 of the general method. MS (ESI, cation) m / z 683.3 (M + H) ⁺ .

Step 4: (1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-Chloro-11 ', 12'-dimethyl-7'-(2-methoxylpropoxy ) -7 '-((4- (3-oxetanyl) -1-piperazinyl) methyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-[20 ] Oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraene] -15'- On 13 ', 13'-dioxide

The reaction was carried out according to the procedure for general method 8. MS (ESI, cation) m / z 809.2 (M + H) ⁺ .

Examples 362 and 363

(1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-12 '-((2S) -2-hydroxypropyl) -7'-methoxy -11'-Methyl-7 '-((9aR) -octahydro-2H-pyrido [1,2-a] pyrazin-2-ylmethyl) -3,4-dihydro-2H, 15'H-spiro [Naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ 0.19 ~ 24,24] pentacosa [8,16,18 Tetraene] -15'-one 13 ', 13'-dioxide and (1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-12 '-((2R) -2-hydroxypropyl) -7'-methoxy-11'-methyl-7'-((9aR) -octahydro-2H-pyrido [1,2-a] pyrazine-2 -Ylmethyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diaza tetracyclo [14.7.2.0-3] , 6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraene] -15'-on 13 ', 13'-dioxide

((1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-methoxy-11'-methyl-7 '-((9aR)- Octahydro-2H-pyrido [1,2-a] pyrazin-2-ylmethyl) -13 ', 13'-dioxid-15'-oxo-3,4-dihydro-2H-spiro [naphthalene- 1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] Tetraene] -12'-yl) acetaldehyde (Example 360) (32 mg, 0.040 mmol) was dissolved in THF (2.0 mL) and cooled to 0 ° C. Methylmagnesium bromide (3.4 M in 2-MeTHF, 0.12 mL, 0.40 mmol) was added dropwise and stirred for 45 minutes. The reaction was quenched with saturated ammonium chloride (15 mL) and the mixture was extracted twice with EtOAc (30 mL). The combined organic layers were washed with brine (1 x 20 mL) and then dried over sodium sulfate. The mixture was then preparative SCF chromatography (4FBSA, 250 mm x 21 mm column; Phenomenex, Torrance, CA; 28 g / min MeOH (+20 mM NH ₃ ) + 42 g / min CO ₂ on Thar 200 SFC ; Outlet pressure = 100 bar; temperature = 40 ° C; wavelength = 220 nm; purified by 28 mL / 3 mL (9.3 mg / mL) MeOH sample solution (3 mL) in 1.1 mL increments) (1S, 3 'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-12'-((2S) -2-hydroxypropyl) -7'-methoxy-11'- Methyl-7 '-((9aR) -octahydro-2H-pyrido [1,2-a] pyrazin-2-ylmethyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1 , 22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetra En] -15'-one 13 ', 13'-dioxide or (1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-12'-(( 2R) -2-hydroxypropyl) -7'-methoxy-11'-methyl-7 '-((9aR) -octahydro-2H-pyrido [1,2-a] pyrazin-2-ylmethyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] A [1,14] diaza tetracyclo [14.7.2.0-3,6-0.0-19,24-] pentacosa [8,16,18,24] tetraene] -15'-one 13 ', 13 '-Dioxide (Example 362, first eluting isomer, t _R = 3.19 min on analytical SFC; 4FBSA; 40% MeOH (+20 mM NH _{3 in} CO ₂ ), de is> 99.5%) Obtained (6.2 mg, 7.7 μmol, 19% yield). MS (ESI, cation) m / z 809.4 (M + H) ⁺ . And (1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-12 '-((2S) -2-hydroxypropyl) -7'-meth Toxy-11'-methyl-7 '-((9aR) -octahydro-2H-pyrido [1,2-a] pyrazin-2-ylmethyl) -3,4-dihydro-2H, 15'H- Spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6-0.0-19,24-] pentacosa [8,16, 18,24] tetraen] -15'-one 13 ', 13'-dioxide or (1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro- 12 '-((2R) -2-hydroxypropyl) -7'-methoxy-11'-methyl-7'-((9aR) -octahydro-2H-pyrido [1,2-a] pyrazine- 2-ylmethyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0 ~ 3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraen] -15'-on 13 ', 13'-dioxide (Example 363, second eluting isomer; T _R = 6.49 min on Analytical SFC; 4FBSA; 40% MeOH (+20 mM NH _{3 in} CO ₂ ), de is> 99.5% (13 mg, 0.016 mmol, 39% yield). MS (ESI, cation) m / z 809.4 (M + H) ⁺ .

Examples 364 and 366

(1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7 '-((9aS) -hexahydropyrazino [2,1-c] [1, 4] oxazine-8 (1H) -ylmethyl) -7'-methoxy-11'-methyl-3,4-dihydro-2H, 16'H-spiro [naphthalene-1,23 '-[21] Oxa [27] thia [1,15] diazeptacyclo [15.7.2.1-12,15 ~ .0-3,6 ~ .0-20,25 ~] heptacosa [8,17,19,25] Tetraene] -16'-one 27 ', 27'-dioxide and (1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-12'-(2- Chloroethyl) -7 '-((9aS) -hexahydropyrazino [2,1-c] [1,4] oxazin-8 (1H) -ylmethyl) -7'-methoxy-11'-methyl -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6]. 0-19,24-] pentacosa [8,16,18,24] tetraene] -15'-on 13 ', 13'-dioxide

Step 1: 2-((1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7 '-((9aS) -hexahydropyrazino [2,1 -c] [1,4] oxazine-8 (1H) -ylmethyl) -7'-methoxy-11'-methyl-13 ', 13'-dioxido-15'-oxo-3,4- Dihydro-2H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6-0.0-19,24-] pentacosa [8,16,18,24] tetraen] -12'-yl) ethyl methanesulfonate

(1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7 '-((9aS) -hexahydropyrazino [2,1-c] [1, 4] oxazine-8 (1H) -ylmethyl) -12 '-(2-hydroxyethyl) -7'-methoxy-11'-methyl-3,4-dihydro-2H, 15'H-spiro [Naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ 0.19 ~ 24,24] pentacosa [8,16,18 Tetraen] -15'-one 13 ', 13'-dioxide (Example 346) (15 mg, 0.018 mmol) was dissolved in DCM (1.0 mL) and Hunig's base; 0.011 mL, 0.064 mmol) and mesyl chloride (3.7 μL, 0.048 mmol) were added. The reaction mixture was stirred for 1.5 hours to almost complete the reaction. The mixture was then diluted with DCM (20 mL) and water (15 mL). The layers were separated and the organic layer was dried over sodium sulfate. The filtrate was concentrated to dryness in vacuo to afford 2-((1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7 '-((9aS) -hexahydropyrazino [2,1-c] [1,4] oxazine-8 (1H) -ylmethyl) -7'-methoxy-11'-methyl-13 ', 13'-dioxido-15'-oxo- 3,4-Dihydro-2H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diaza tetracyclo [14.7.2.0-3,6-0.0-19,24 ~] Pentacosa [8,16,18,24] tetraen] -12'-yl) ethyl methanesulfonate was obtained (16 mg, 0.018 mmol, 100% yield) and used directly for these next reactions. MS (ESI, cation) m / z 875.3 (M + H) ⁺ .

 Step 2: (1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7 '-((9aS) -hexahydropyrazino [2,1-c] [1,4] oxazine-8 (1H) -ylmethyl) -7'-methoxy-11'-methyl-3,4-dihydro-2H, 16'H-spiro [naphthalene-1,23'- [21] oxa [27] thia [1,15] diazeptacyclo [15.7.2.1-12,15 ~ .0-3,6 ~ .0 ~ 20,25 ~] heptacosa [8,17,19 , 25] tetraene] -16'-one 27 ', 27'-dioxide and (1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-12'- (2-Chloroethyl) -7 '-((9aS) -hexahydropyrazino [2,1-c] [1,4] oxazin-8 (1H) -ylmethyl) -7'-methoxy-11 '-Methyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3, 6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraene] -15'-on 13 ', 13'-dioxide

2-((1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7 '-((9aS) -hexahydropyrazino [2,1-c] [1,4] oxazine-8 (1H) -ylmethyl) -7'-methoxy-11'-methyl-13 ', 13'-dioxido-15'-oxo-3,4-dihydro- 2H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6-0.0-19,24-] pentacosa [8, 16,18,24] tetraen] -12'-yl) ethyl methanesulfonate (16 mg, 0.018 mmol) was dissolved in acetonitrile (1.0 mL) and tetrabutylammonium difluoro-triphenylsilicate (59 mg, 0.11 mmol) was added. The reaction was then heated at 75 ° C. to complete the reaction. The reaction was then cooled to room temperature and diluted with EtOAc (25 mL) and water (20 mL). The layers were separated and the organic layer was washed again with water (1 x 20 mL) and brine (1 x 20 mL) and dried over sodium sulfate. The crude product was then purified by medium pressure chromatography (silica; 0% to 100% gradient of 10% 2 M ammonia dissolved in MeOH in DCM) to give two products: (1S, 3'R , 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7 '-((9aS) -hexahydropyrazino [2,1-c] [1,4] oxazine-8 (1H) -ylmethyl) -7'-methoxy-11'-methyl-3,4-dihydro-2H, 16'H-spiro [naphthalene-1,23 '-[21] oxa [27] thia [ 1,15] diazaptacyclo [15.7.2.1--12,15-.0-3,6-.0-20,25-] heptacosa [8,17,19,25] tetraene] -16 ' -One 27 ', 27'-dioxide (Example 364) (4.9 mg, 6.3 μmol, 34% yield), MS (ESI, cation) m / z 779.3 (M + H) ⁺ ; And (1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-12 '-(2-chloroethyl) -7'-((9aS) -hexahydropyra Zino [2,1-c] [1,4] oxazine-8 (1H) -ylmethyl) -7'-methoxy-11'-methyl-3,4-dihydro-2H, 15'H-spiro [Naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18 Tetraen] -15'-one 13 ', 13'-dioxide (Example 366) (3.5 mg, 4.29 μmol, 23% yield), MS (ESI, cation) m / z 815.3 (M + H) ⁺ .

Examples 358, 359, and 367

(1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-Chloro-12 '-(2-hydroxyethyl) -7'-methoxy-11'- Methyl-7 '-((9aR) -octahydro-2H-pyrido [1,2-a] pyrazin-2-ylmethyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1 , 22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetra N] -15'-one 13 ', 13'-dioxide (Example 358) and (1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro- 7'-methoxy-11'-methyl-12 '-(2-(((2-methyl-2-propanyl) (diphenyl) silyl) oxy) ethyl) -7'-((9aR) -octahydro -2H-pyrido [1,2-a] pyrazin-2-ylmethyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diaza tetracyclo [14.7.2.0-3,6-0.0-19,24-] pentacosa [8,16,18,24] tetraene] -15'-one 13 ', 13' -Dioxide (Example 359) and (1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-12 '-(2- (dimethylamino) ethyl ) -7'-methoxy-11'-methyl-7 '-((9aR) -octahydro-2H-pyrido [1,2-a] pyrazine-2- Methyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 0.19 ~ 24 ~] Pentacosa [8,16,18,24] tetraene] -15'-on 13 ', 13'-dioxide (Example 367)

Step 1: (3R, 4S) -1-hydroxy-N, N-bis (4-methoxybenzyl) -4-methyl-6-heptene-3-sulfonamide

N-butyllithium (2.8 g, 6.9 mmol) in a solution of (S) -N, N-bis (4-methoxybenzyl) -2-methylpent-4-ene-1-sulfonamide (2.8 g, 6.9 mmol) in THF (15 mL) 2.5 M in hexanes, 3.1 mL, 7.6 mmol) was added dropwise at -78 ° C. The mixture was stirred at -78 ° C for 5 minutes and ethylene oxide (2.5 M in THF, 5.6 mL, 14 mmol) was added. The mixture was warmed to ambient temperature and stirred for 18 hours. The mixture was quenched with saturated aqueous NH ₄ Cl and extracted twice with EtOAc. The organic layer was washed with brine, dried (MgSO ₄ ) and filtered. The filtrate was concentrated and the resulting residue was separated by chromatography (silica gel; 20% to 60% EtOAc in hexanes) to give a diastereomeric mixture of the title compound. The mixture was then preparative SFC chromatography (ChiralPak IC-H 250 mm x 30 mm column, Phenomenex, Torrance, CA; 35 g / min MeOH + 105 g / min CO ₂ on Thar 200 SFC; output pressure = 100 bar; Temperature = 22 ° C., Wavelength = 215 nm; Purified with 25,000 mg / 50 mL (500 mg / mL) of MeOH sample solution (50 mL) in 1.0 mL) as (3R, 4S)-as a slowly eluting isomer. 1-hydroxy-N, N-bis (4-methoxybenzyl) -4-methyl-6-heptene-3-sulfonamide was obtained as a yellow liquid (t _R = 2.51 min on analytical SFC; IC-H Column; 25% MeOH in CO ₂ ) de was 100%. ¹ H NMR (400 MHz, Dichloromethane-d2) δ ppm 7.24 (d, J = 8.61 Hz, 4H), 6.90 (d, J = 8.61 Hz, 4H), 5.62 (ddt, J = 16.75, 10.20, 7.07 , 7.07 Hz, 1H), 5.08 (s, 1H), 5.05 (br d, J = 7.83 Hz, 1H), 4.39 (d, J = 15.26 Hz, 2H), 4.23 (d, J = 15.26 Hz, 2H) , 3.83 (s, 6H), 3.66-3.81 (m, 2H), 3.00-3.16 (m, 1H), 1.97-2.23 (m, 3H), 1.79-1.96 (m, 3H), 1.06 (d, J = 6.85 Hz, 3H). MS (ESI, cation) m / z 470.2 (M + Na) ⁺ .

Step 2: (3R, 4S) -N, N-bis (4-methoxybenzyl) -4-methyl-1-(((2-methyl-2-propaneyl) (diphenyl) silyl) oxy) -6 -Heptene-3-sulfonamide

(3R, 4S) -1-hydroxy-N, N-bis (4-methoxybenzyl) -4-methylhept-6-ene-3-sulfonamide (6.4 g, 14 mmol) in DMF (34 mL) Dissolved in. Imidazole (1.7 g, 24 mmol) and tert-butylphenylsilyl chloride (6.3 mL, 24 mmol) were added and the mixture was stirred for 45 minutes. The reaction was then quenched with saturated ammonium chloride solution (150 mL) and extracted with EtOAc (1 × 300 mL). The layers were separated and the organic layer was washed with 1 N LiCl solution (1 x 100 mL), 1 N HCl solution (1 x 100 mL) and brine (1 x 100 mL) and then dried over magnesium sulfate. The crude product was then purified by medium pressure chromatography (silica; 5% to 100% EtOAc in heptane) to (3R, 4S) -N, N-bis (4-methoxybenzyl) -4-methyl-1- (((2-methyl-2-propanyl) (diphenyl) silyl) oxy) -6-heptene-3-sulfonamide was obtained (9.70 g, 14.14 mmol, 98% yield). ¹ H NMR (400 MHz, Chloroform-d) δ 7.67 (dt, J = 1.5, 7.3 Hz, 4H), 7.47-7.35 (m, 6H), 7.16 (d, J = 8.8 Hz, 4H), 6.79-6.78 ( m, 1H), 6.81 (d, J = 8.6 Hz, 3H), 5.56 (tdd, J = 7.0, 10.1, 17.0 Hz, 1H), 4.97 (dd, J = 1.8, 10.0 Hz, 1H), 4.91 (dd , J = 1.6, 17.0 Hz, 1H), 4.31-4.10 (m, 4H), 3.84-3.80 (m, 1H), 3.78 (s, 6H), 3.77-3.72 (m, 1H), 3.09 (ddd, J = 1.6, 4.2, 7.4 Hz, 1H), 2.22-2.07 (m, 2H), 1.98-1.79 (m, 3H), 1.07 (s, 9H), 1.02 (d, J = 6.8 Hz, 3H). MS (ESI, cation) m / z 708.3 (M + Na) ⁺ .

Step 3: (3R, 4S) -4-methyl-1-(((2-methyl-2-propaneyl) (diphenyl) silyl) oxy) -6-heptene-3-sulfonamide

In a 1000 mL flask cooled to 0 ° C., (3R, 4S) -N, N-bis (4-methoxybenzyl) -4-methyl-1-(((2-methyl-2-propaneyl) (diphenyl ) Silyl) oxy) -6-heptene-3-sulfonamide (9.4 g, 14 mmol), DCM (290 mL) and anisole (7.5 mL, 69 mmol) were added followed by trifluoroacetic acid (49 mL). Added. The reaction was warmed to room temperature overnight to complete the reaction. Then, the reaction mixture was concentrated using a rotovap so that the volume of the reaction mixture was ˜25 mL. The crude product was then purified by medium pressure chromatography (silica; 10% to 50% EtOAc in heptane) to give (3R, 4S) -4-methyl-1-(((2-methyl-2-propanyl) ( Diphenyl) silyl) oxy) -6-heptene-3-sulfonamide was obtained (2.7 g, 6.1 mmol, 44% yield). ¹ H NMR (400 MHz, Chloroform-d) δ 7.67 (ddd, J = 1.5, 5.8, 7.2 Hz, 4H), 7.49-7.37 (m, 6H), 5.72 (tdd, J = 6.9, 10.1, 17.0 Hz, 1H ), 5.06-4.94 (m, 2H), 4.41 (br s, 2H), 3.93-3.80 (m, 2H), 3.23-3.16 (m, 1H), 2.46 (m, 1H), 2.13-2.06 (m, 1H), 2.05-2.01 (m, 1H), 1.91 (dtd, J = 3.7, 7.1, 14.7 Hz, 2H), 1.07 (s, 9H), 1.02 (d, J = 7.0 Hz, 3H). MS (ESI, cation) m / z 468.2 (M + Na) ⁺ .

Step 4: (3S) -6'-Chloro-5-(((1R, 2R) -2-((1S) -1-hydroxy-2-propen-1-yl) cyclobutyl) methyl) -N -(((3R, 4S) -4-methyl-1-(((2-methyl-2-propanyl) (diphenyl) silyl) oxy) -6-hepten-3-yl) sulfonyl) -3 ' , 4,4 ', 5-tetrahydro-2'H-spiro [1,5-benzoxazepine-3,1'-naphthalene] -7-carboxamide

The reaction was carried out according to the procedure for general method 1 (R ¹ = H). MS (ESI, cation) m / z 895.3 (M + H) ⁺ .

Step 5: (1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-Chloro-7'-hydroxy-11'-methyl-12 '-(2-(( (2-methyl-2-propanyl) (diphenyl) silyl) oxy) ethyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] Thia [1,14] diaza tetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraen] -15'-one 13 ', 13 '-Dioxide

The reaction was carried out according to the procedure for general method 1 (R ¹ = H). MS (ESI, cation) m / z 867.3 (M + H) ⁺ .

Step 6: (1S, 3'R, 6'R, 8'E, 11'S, 12'R) -6-Chloro-11'-methyl-12 '-(2-(((2-methyl-2-prop Panyl) (diphenyl) silyl) oxy) ethyl) -3,4-dihydro-2H, 7'H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1, 14] diatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraene] -7 ', 15'-dione 13', 13 '-Dioxide

The reaction was carried out according to the procedure for general method 1 (R ¹ = H). MS (ESI, cation) m / z 865.3 (M + H) ⁺ .

Step 7: (1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7 '-(hydroxymethyl) -7'-methoxy-11' -Methyl-12 '-(2-(((2-methyl-2-propanyl) (diphenyl) silyl) oxy) ethyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1 , 22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetra EN] -15'-one 13 ', 13'-dioxide

The reaction was carried out according to the procedure for general method 3 (R ⁴ = Me). MS (ESI, cation) m / z 911.4 (M + H) ⁺ .

Step 8: (1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-Chloro-7'-methoxy-11'-methyl-12 '-(2- (((2-methyl-2-propanyl) (diphenyl) silyl) oxy) ethyl) -15'-oxo-3,4-dihydro-2H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraene] -7'-carbaldehyde 13 ', 13'-dioxide

The reaction was carried out according to the procedure for general method 3 (R ⁴ = Me). MS (ESI, cation) m / z 909.3 (M + H) ⁺ .

Step 9: (1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-methoxy-11'-methyl-12 '-(2- (((2-methyl-2-propanyl) (diphenyl) silyl) oxy) ethyl) -7 '-((9aR) -octahydro-2H-pyrido [1,2-a] pyrazin-2-yl Methyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 0.19 ~ 24 ~] Pentacosa [8,16,18,24] tetraene] -15'-on 13 ', 13'-dioxide (Example 359)

The reaction was carried out according to the procedure for general method 8. MS (ESI, cation) m / z 1033.3 (M + H) ⁺ .

Step 10: (1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-Chloro-12 '-(2-hydroxyethyl) -7'-methoxy- 11'-Methyl-7 '-((9aR) -octahydro-2H-pyrido [1,2-a] pyrazin-2-ylmethyl) -3,4-dihydro-2H, 15'H-spiro [ Naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18, 24] tetraen] -15'-on 13 ', 13'-dioxide (Example 358)

(1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-methoxy-11'-methyl-12 '-(2-((( 2-methyl-2-propanyl) (diphenyl) silyl) oxy) ethyl) -7 '-((9aR) -octahydro-2H-pyrido [1,2-a] pyrazin-2-ylmethyl)- 3,4-Dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6-0.0 19,24-] Pentacosa [8,16,18,24] tetraene] -15'-one 13 ', 13'-dioxide (Example 359) (38 mg, 0.037 mmol) was converted to THF (1.0 mL). Dissolved in. Tetrabutylammonium fluoride (1.0 M in THF, 1.1 mL, 1.1 mmol) was then added and the reaction stirred for 24 hours to complete the reaction. The reaction mixture was diluted with DCM and then added directly onto the column and purified by medium pressure chromatography (silica; 0% to 100% (maintain) of (10% 2 M ammonia: DCM): DCM dissolved in MeOH). The product contaminated with tetrabutylammonium fluoride was obtained. The mixture was then diluted with water (50 mL) and EtOAc (20 mL). The layers were then separated and the organic layer was washed again with water (1 x 50 mL) to remove the remaining tetrabutylammonium fluoride. The organic layer was then washed with brine (1 x 15 mL) and dried over sodium sulfate. The slurry was filtered and the filtrate was concentrated to (1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-12 '-(2-hydroxyethyl) -7 '-Methoxy-11'-methyl-7'-((9aR) -octahydro-2H-pyrido [1,2-a] pyrazin-2-ylmethyl) -3,4-dihydro-2H, 15 'H-spiro [naphthalene-1,22'-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6-0.0-19,24-] pentacosa [8 , 16,18,24] tetraen] -15'-one 13 ', 13'-dioxide (Example 358) was obtained (150 mg, 0.18 mmol, 61% yield). MS (ESI, cation) m / z 795.3 (M + H) ⁺ .

Step 11: 2-((1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-methoxy-11'-methyl-7'- ((9aR) -octahydro-2H-pyrido [1,2-a] pyrazin-2-ylmethyl) -13 ', 13'-dioxido-15'-oxo-3,4-dihydro-2H Spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6-0.0-19,24-] pentacosa [8,16 , 18,24] tetraen] -12'-yl) ethyl methanesulfonate

(1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-Chloro-12 '-(2-hydroxyethyl) -7'-methoxy-11'- Methyl-7 '-((9aR) -octahydro-2H-pyrido [1,2-a] pyrazin-2-ylmethyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1 , 22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetra En] -15'-one 13 ', 13'-dioxide (Example 358) (50 mg, 0.063 mmol) was dissolved in DCM (3.0 mL) and Huig's base (66 μL, 0.38 mmol) and mesyl chloride (21). μL, 0.26 mmol) was added. The reaction mixture was stirred for 1.5 hours to complete the reaction. The mixture was then diluted with DCM (20 mL) and water (25 mL). The layers were separated and the organic layer was washed again with water (25 mL) and then dried over sodium sulfate. The filtrate was concentrated to dryness in vacuo to afford 2-((1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-methoxy-11'-methyl -7 '-((9aR) -octahydro-2H-pyrido [1,2-a] pyrazin-2-ylmethyl) -13', 13'-deoxido-15'-oxo-3,4- Dihydro-2H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6-0.0-19,24-] pentacosa [8,16,18,24] tetraen] -12'-yl) ethyl methanesulfonate (63 mg) was obtained. MS (ESI, cation) m / z 873.3 (M + H) ⁺ .

Step 12: (1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-Chloro-12 '-(2- (dimethylamino) ethyl) -7'- Methoxy-11'-methyl-7 '-((9aR) -octahydro-2H-pyrido [1,2-a] pyrazin-2-ylmethyl) -3,4-dihydro-2H, 15'H Spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6-0.0-19,24-] pentacosa [8,16 Tetraene] -15'-on 13 ', 13'-dioxide (Example 367)

In a vial, 2-((1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-methoxy-11'-methyl-7 '-((9aR) -octahydro-2H-pyrido [1,2-a] pyrazin-2-ylmethyl) -13', 13'-dioxido-15'-oxo-3,4-dihydro -2H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6-0.0-19,24-] pentacosa [8 , 16,18,24] tetraen] -12'-yl) ethyl methanesulfonate (30 mg, 0.34 mmol), dimethylamine (2M in THF, 0.17 mL, 0.34 mmol), potassium carbonate (95 mg, 0.69 mmol) and catalytic amounts of potassium iodide were dissolved in acetonitrile (1.0 mL) and sealed with a pressure cap. The reaction mixture was then heated at 65 ° C. for 40 minutes to complete the reaction. The reaction was then diluted with DCM and filtered through fine glass frit. The filtrate was then concentrated and the residue was preparative SFC chromatography (Kromasil Cyano 250 mm x 21 mm column; 17.5 g / min MeOH (+20 mM ammonia) + 52.5 g / min CO ₂ on Thar 200 SFC; output pressure = 100 bar; temperature = 22 ° C; wavelength = 215 nm; purified with 31 mg / 4 mL (7.8 mg / mL) of MeOH sample solution (4 mL) injected in 1.0 mL) (1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-12 '-(2- (dimethylamino) ethyl) -7'-methoxy-11'-methyl-7' -((9aR) -octahydro-2H-pyrido [1,2-a] pyrazin-2-ylmethyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'- [20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraene] -15 '-On 13', 13'-dioxide (Example 367) was obtained as a slowly eluting peak (t _R = 2.90 min on analytical SFC; Kromasil Cyano column; 25% MeOH in CO ₂ ) 97.8% purity (4.7 mg, 5.7 mmol, 17% yield). MS (ESI, cation) m / z 822.3 (M + H) ⁺ .

Examples 399 and 400

(1S, 3'R, 6'R, 7'R, 9a ''S, 11'S, 12'R) -6-chloro-11', 12'-dimethyl-3,4,6 '', 7 ' ', 9' ', 9a' '-hexahydro-1''H, 2H, 15'H-dicespiro [naphthalene-1,22'-[20] oxa [13] thia [1,14] diazate Cyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [16,18,24] triene-7 ', 3' '-[1,4] oxazino [3,4-c ] [1,4] oxazine] -15'-one 13 ', 13'-dioxide and (1S, 3'R, 6'R, 7'S, 9a''S, 11'S, 12'R) -6-chloro -11 ', 12'-dimethyl-3,4,6' ', 7' ', 9' ', 9a' '-hexahydro-1''H, 2H, 15'H-dicespiro [naphthalene-1 , 22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [16,18,24] triene- 7 ', 3' '-[1,4] oxazino [3,4-c] [1,4] oxazine] -15'-one 13', 13'-dioxide

Step 1: (1S, 3'R, 6'R, 7'R, 11'S, 12'R) -6-chloro-7'-hydroxy-7 '-(((3R) -3- (hydroxymethyl ) -4-morpholinyl) methyl) -11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-[20] oxa [13] thia [1,14] diazeptracyclo [14.7.2.0-3,6-0.0-19,24-] pentacosa [16,18,24] triene] -15'-one 13 ', 13'-dioxide And (1S, 3'R, 6'R, 7'S, 11'S, 12'R) -6-chloro-7'-hydroxy-7 '-(((3R) -3- (hydroxymethyl) -4- Morpholinyl) methyl) -11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-[20] oxa [13] thia [1,14 ] Diazettracyclo [14.7.2.0 ~ 3,6 ~ .0 ~ 19,24 ~] pentacosa [16,18,24] triene] -15'-one 13 ', 13'-dioxide

A glass microwave reaction vessel (1S, 3'R, 6'R, 11'S, 12'R) -6-chloro-11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-dice Fatigue [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [16,18, 24] trien-7 ', 2''-oxirane]-15'-one13',13'-dioxide (0.300 g, 0.489 mmol) and 3 (R) -hydroxymethylmorpholine (0.650 g, 5.55 mmol; Matrix Sci., Elgin, SC). Ethanol (3 mL) and triethylamine (1.8 mL, 12.9 mmol) were added and the reaction mixture was sealed under argon and heated to 90 ° C. for a total of 27 hours in an Initiator microwave reactor. The reaction was heated for an additional 16 hours in a microwave reactor. The reaction mixture was purified by reverse phase HPLC (Gilson; Gemini-NX 10 μm, C18, AXIA, 100 × 50 mm column) (H ₂ O (containing 0.1% TFA): eluted with CH ₃ CN (containing 0.1% TFA) 9: 1 → 1: 9 gradient) The fractions containing the desired product were combined and partitioned into pH 7 buffer (1 M K2HPO4 / KH2PO4) / EtOAc The aqueous layer was extracted with EtOAc (3x) and the combined organic layers were washed with brine and , Na ₂ SO ₄ and filtered and dried in. and the filtrate was concentrated under reduced pressure to give (1S, 3'R, 6'R, 7'R , 11'S, 12'R) -6- chloro -7'- -hydroxy-7 '-(((3R) -3- (hydroxymethyl) -4-morpholinyl) methyl) -11', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene -1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [16,18,24] tree N] -15'-one 13 ', 13'-dioxide and (1S, 3'R, 6'R, 7'S, 11'S, 12'R) -6-chloro-7'-hydroxy-7'-(( (3R) -3- (hydroxymethyl) -4-morpholinyl) methyl) -11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[ 20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [16,18,24] triene] -15'-one A mixture of 13 ', 13'-dioxide was obtained as a white crystalline solid (177 mg, 50%).

Step 2: (1S, 3'R, 6'R, 7'R, 9a ''S, 11'S, 12'R) -6-chloro-11', 12'-dimethyl-3,4,6 '' , 7 '', 9 '', 9a ''-hexahydro-1''H, 2H, 15'H-dicespiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] Diazatetracyclo [14.7.2.0 ~ 3,6 ~ .0 ~ 19,24 ~] Pentacosa [16,18,24] triene-7 ', 3' '-[1,4] oxazino [3, 4-c] [1,4] oxazine] -15'-on 13 ', 13'-dioxide and (1S, 3'R, 6'R, 7'S, 9a''S, 11'S, 12'R)- 6-chloro-11 ', 12'-dimethyl-3,4,6' ', 7' ', 9' ', 9a' '-hexahydro-1''H, 2H, 15'H-dicespiro [ Naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [16,18,24] Triene-7 ', 3' '-[1,4] oxazino [3,4-c] [1,4] oxazine] -15'-one 13', 13'-dioxide

(1S, 3'R, 6'R, 7'R, 11'S, 12'R) -6-chloro-7'-hydroxy-7 '-(((3R) -3- (hydroxymethyl) -4 -Morpholinyl) methyl) -11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-[20] oxa [13] thia [1, 14] diazettracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [16,18,24] triene] -15'-one 13 ', 13'-dioxide and tetrahydro (1S, 3'R, 6'R, 7'S, 11'S, 12'R) -6-chloro-7'-hydroxy-7 '-(((3R) -3- (hydroxy) in furan (4 mL) Methyl) -4-morpholinyl) methyl) -11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-[20] oxa [13] Thia [1,14] diaza tetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [16,18,24] triene] -15'-one 13 ', 13'- To a room temperature mixture of dioxide (0.136 g, 0.186 mmol) was added sodium hydride (0.050 g, 1.250 mmol), a 60% dispersion in mineral oil, and the reaction was stirred for 30 minutes. To the reaction was added p-toluenesulfone anhydride (0.250 g, 0.766 mmol) and the reaction stirred for 5.5 h. To the reaction was added sodium hydride (0.050 g, 1.250 mmol), a 60% dispersion in mineral oil, and the reaction was stirred overnight. To the reaction was added p-toluenesulfone anhydride (0.180 g) and the reaction was stirred for 24 hours. To the reaction was added sodium hydride (0.050 g, 1.25 mmol), a 60% dispersion in mineral oil, and the reaction was stirred for an additional 24 hours. The reaction was quenched with pH 7 buffer (1 M K2HPO4 / KH2PO4) and the aqueous layer was extracted three times with EtOAc. The combined organic layers were washed with brine and the filtrate was purified by reverse phase HPLC (Gilson; Gemini-NX C18 AXIA, 100 x 50 mm column) (H ₂ O (containing 0.1% TFA): CH ₃ CN (containing 0.1% TFA). Eluting with a gradient of 9: 1 to 1: 9 The fractions containing the desired product were combined and partitioned into pH 7 buffer (1 M K2HPO4 / KH2PO4) / EtOAc The aqueous layer was extracted with EtOAc (3 ×) and the combined organic layers were Washed with brine, dried over Na ₂ SO ₄ and filtered The filtrate was concentrated under reduced pressure to give 118 mg (89%) of a white solid, which was purified by achiral SFC chromatography (1S, 3'R, 6'R, 7'R, 9a ''S, 11'S, 12'R) -6-chloro-11', 12'-dimethyl-3,4,6 '', 7 '', 9 '', 9a ''-hexahydro-1''H, 2H, 15'H-dicespiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7 .2.0 ~ 3,6 ~ .0 ~ 19,24 ~] Pentacosa [16,18,24] triene-7 ', 3''-[1,4] oxazino [3,4-c] [1 , 4] oxazine] -15'-one 13 ', 13'-dioxide or (1S, 3'R, 6'R, 7'S, 9a''S, 1 1'S, 12'R) -6-chloro-11 ', 12'-dimethyl-3,4,6'',7'',9'',9a''-hexahydro-1''H, 2H, 15'H-dicespiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6-0.0-19,24-] pentacosa [16,18,24] triene-7 ', 3''-[1,4] oxazino [3,4-c] [1,4] oxazine] -15'-on 13', 13'- Dioxide was obtained as a white crystalline solid (10 mg, 8%, first eluted peak) m / z (ESI, cation) 712.7 (M + 1) ⁺ .The second eluting compound was (1S, 3'R, 6'R, 7'R, 9a ''S, 11'S, 12'R) -6-chloro-11', 12'-dimethyl-3,4,6 '', 7 '', 9 '', 9a ''-hexahydro-1''H, 2H, 15'H-dicespiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7 .2.0 ~ 3,6 ~ .0 ~ 19,24 ~] Pentacosa [16,18,24] triene-7 ', 3''-[1,4] oxazino [3,4-c] [1 , 4] oxazine] -15'-one 13 ', 13'-dioxide or (1S, 3'R, 6'R, 7'S, 9a''S, 11'S, 12'R) -6-chloro-11 ' , 12'-dimethyl-3,4,6 '', 7 '', 9 '', 9a ''-hexahydro-1''H, 2H, 15'H-dicespiro [naphthal Len-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [16,18,24] Triene-7 ', 3''-[1,4] oxazino [3,4-c] [1,4] oxazine] -15'-one 13', 13'-dioxide, white crystalline solid Was isolated (12 mg, 9%, second eluted peak). (ESI, cation) m / z 712.6 (M + l) ⁺ .

Example 405

(1S, 3'R, 6'R, 7'S, 10'S, 11'S) -6-chloro-7 '-((9aS) -hexahydropyrazino [2,1-c] [1,4] oxazine-8 (1H) -ylmethyl) -7'-hydroxy-10 ', 11'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-[20] oxa [ 13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [16,18,24] triene] -15'-one 13 ', 13 '-Dioxide

The vial was taken from (1S, 3'R, 6'R, 7'S, 8'E, 10'S, 11'S) -6-chloro-7 '-((9aS) -hexahydropyrazino [2,1-c] [1, 4] oxazine-8 (1H) -ylmethyl) -7'-hydroxy-10 ', 11'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22' [20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraene]- 15'-one 13 ', 13'-dioxide (0.012 g, 0.016 mmol) and platinum (IV) oxide (0.4 mg, 1.6 μmol) were charged. Ethanol (2 mL) and methanol (0.3 mL) were added. The reaction was flushed with nitrogen for 5 minutes and then exhausted / nitrogen backfill was repeated three times. The reaction was stirred overnight at room temperature under 20 psi of nitrogen. The reaction was flushed with nitrogen. Ethanol (5 mL) and DCM (5 mL) were added. The reaction was flushed with nitrogen and then evacuated / nitrogen backfilled three times. The reaction was stirred for 24 hours at room temperature under 20 psi of nitrogen. The reaction was flushed with nitrogen, filtered through celite and rinsed with ethyl acetate. The filtrate was concentrated under reduced pressure and purified by silica gel flash chromatography using MeOH in DCM in a gradient of 0% to 10% to give the title compound (0.007 g, 9 μmol, 58% yield). MS (ESI, cation) m / z 755.2 (M + H) ⁺ .

Example 466

(1S, 3'R, 6'R, 7'R, 11'S, 12'R) -6-chloro-11 ', 12'-dimethyl-4' '-(methylsulfonyl) -3,4-di Hydro-2H, 15'H-dicespiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 Pentacosa [16,18,24] triene-7 ', 2' '-[1,4] oxazinane] -15'-one 13', 13'-dioxide and (1S, 3'R, 6 'R, 7'S, 11'S, 12'R) -6-chloro-11', 12'-dimethyl-4 ''-(methylsulfonyl) -3,4-dihydro-2H, 15'H-dicespiro [Naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [16,18,24 ] Trien-7 ', 2' '-[1,4] oxazinane] -15'-one 13', 13'-dioxide

In THF (1.5 mL) in a microwave reaction vessel, (1S, 3'R, 6'R, 7'R, 11'S, 12'R) -6-chloro-7'-hydroxy-7 '-((( 2-hydroxyethyl) amino) methyl) -11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-[20] oxa [13] thia [1,14] diazeptracyclo [14.7.2.0-3,6-0.0-19,24-] pentacosa [16,18,24] triene] -15'-one 13 ', 13'-dioxide And (1S, 3'R, 6'R, 7'S, 11'S, 12'R) -6-chloro-7'-hydroxy-7 '-(((2-hydroxyethyl) amino) methyl) -11' , 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0 ~ 3,6 ~ .0 ~ 19,24 ~] of pentacosa [16,18,24] triene] -15'-one 13 ', 13'-dioxide (Example 452) (34 mg, 0.043 mmol) To the stirred solution was added diisopropylethylamine (0.075 mL, 0.431 mmol) at room temperature under argon followed by methanesulphone anhydride (37.6 mg, 0.216 mmol). The resulting mixture was stirred at room temperature for 5 minutes during which the color of the mixture changed from colorless to pale green yellow. The vessel was capped and the microwave reaction was examined (3 hours at 70 ° C.). Then 4- (dimethylamino) pyridine (15.81 mg, 0.129 mmol) was added followed by further methanesulfone anhydride (18 mg, 0.11 mmol). The vessel was sealed and microwave irradiated again (4 h at 70 ° C.). Remove volatiles, concentrate the concentrate in DMSO and preparative reversed phase HPLC (Gemini ™ Prep C18 5 μm column; Phenomenex, Torrance, CA; eluting with a gradient of 30% to 95% of MeCN in water, both solvents Purified with 0.1% TFA, 25 min method), and after lyophilization, (1S, 3'R, 6'R, 7'R, 11'S, 12'R) -6-chloro-11 ', 12 '-Dimethyl-4''-(methylsulfonyl) -3,4-dihydro-2H, 15'H-dispiro [naphthalene-1,22'-[20] oxa [13] thia [1,14 ] Diazatetracyclo [14.7.2.0 ~ 3,6 ~ .0 ~ 19,24 ~] Pentacosa [16,18,24] triene-7 ', 2''-[1,4] oxazinane]- 15'-one 13 ', 13'-dioxide and (1S, 3'R, 6'R, 7'S, 11'S, 12'R) -6-chloro-11', 12'-dimethyl-4 ''-( Methylsulfonyl) -3,4-dihydro-2H, 15'H-dispiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0 ~ 3,6 ~ .0 ~ 19,24 ~] Pentacosa [16,18,24] Trienne-7 ', 2''-[1,4] Oxazinane] -15'-On 13', 13'- 4.0 mg of white solids As a white solid. MS (ESI, cation) m / z 734.2 (M + l) ⁺ .

Examples 499 and 500

Methyl 3-((9aR) -8-(((1S, 3'R, 6'R, 7'R, 11'S, 12'R) -6-chloro-7'-hydroxy-11 ', 12'- Dimethyl-13 ', 13'-dioxido-15'-oxo-3,4-dihydro-2H-spiro [naphthalene-1,22'-[20] oxa [13] thia [1,14] dia Zatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [16,18,24] trien] -7'-yl) methyl) octahydro-2H-pyrazino [1, 2-a] pyrazin-2-yl) propanoate and methyl 3-((9aR) -8-(((1S, 3'R, 6'R, 7'S, 11'S, 12'R) -6-chloro- 7'-hydroxy-11 ', 12'-dimethyl-13', 13'-dioxido-15'-oxo-3,4-dihydro-2H-spiro [naphthalene-1,22 '-[20 ] Oxa [13] thia [1,14] diatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [16,18,24] triene] -7'-yl) Methyl) octahydro-2H-pyrazino [1,2-a] pyrazin-2-yl) propanoate and methyl 3-((9aS) -8-(((1S, 3'R, 6'R, 7 'R, 11'S, 12'R) -6-chloro-7'-hydroxy-11', 12'-dimethyl-13 ', 13'-dioxido-15'-oxo-3,4-dihydro -2H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] die Zatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [16,18,24] trien] -7'-yl) methyl) octahydro-2H-pyrazino [1, 2-a] pyrazin-2-yl) propanoate and methyl 3-((9aS) -8-(((1S, 3'R, 6'R, 7'S, 11'S, 12'R) -6-chloro- 7'-hydroxy-11 ', 12'-dimethyl-13', 13'-dioxido-15'-oxo-3,4-dihydro-2H-spiro [naphthalene-1,22 '-[20 ] Oxa [13] thia [1,14] diatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [16,18,24] triene] -7'-yl) Methyl) octahydro-2H-pyrazino [1,2-a] pyrazin-2-yl) propanoate (Example 499) and (1S, 3'R, 6'R, 7'R, 11'S, 12 ' R) -7 '-(((9aR) -8-acryloyloctahydro-2H-pyrazino [1,2-a] pyrazin-2-yl) methyl) -6-chloro-7'-hydroxy- 11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-[20] oxa [13] thia [1,14] diazatetracyclo [14.7 .2.0 ~ 3,6 ~ .0 ~ 19,24 ~] Pentacosa [16,18,24] triene] -15'-one 13 ', 13'-dioxide and (1S, 3'R, 6'R , 7'R, 11'S, 12'R) -7 '-(((9a S) -8-acryloyloctahydro-2H-pyrazino [1,2-a] pyrazin-2-yl) methyl) -6-chloro-7'-hydroxy-11 ', 12'-dimethyl- 3,4-Dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6-0.0 ~ 19,24 ~] Pentacosa [16,18,24] triene] -15'-one 13 ', 13'-dioxide and (1S, 3'R, 6'R, 7'S, 11'S, 12'R) -7 '-(((9aR) -8-acryloyloctahydro-2H-pyrazino [1,2-a] pyrazin-2-yl) methyl) -6-chloro-7'-hydroxy-11' , 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0 ~ 3,6 ~ .0 ~ 19,24 ~] Pentacosa [16,18,24] triene] -15'-one 13 ', 13'-dioxide and (1S, 3'R, 6'R, 7'S , 11'S, 12'R) -7 '-(((9aS) -8-acryloyloctahydro-2H-pyrazino [1,2-a] pyrazin-2-yl) methyl) -6-chloro-7 '-Hydroxy-11', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] dia Jatte Cyclo [14.7.2.0 ~ 3,6 ~ .0 ~ 19,24 ~] penta Kosa [16,18,24] triene] -15'- on 13 ', 13'- dioxide (Example 500)

(1S, 3'R, 6'R, 7'R, 11'S, 12'R) -6-chloro-7'-hydroxy-11 ', 12'-dimethyl-7'- in DCM (10 mL) ((9aR) -octahydro-2H-pyrazino [1,2-a] pyrazin-2-ylmethyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[ 20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [16,18,24] triene] -15'-one 13 ', 13'-dioxide, (1S, 3'R, 6'R, 7'R, 11'S, 12'R) -6-chloro-7'-hydroxy-11', 12'-dimethyl-7 '-((9aS) -octahydro-2H-pyrazino [1,2-a] pyrazin-2-ylmethyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22' -[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0 ~ 3,6 ~ .0 ~ 19,24 ~] pentacosa [16,18,24] triene] -15 ' -One 13 ', 13'-dioxide, (1S, 3'R, 6'R, 7'S, 11'S, 12'R) -6-chloro-7'-hydroxy-11', 12'-dimethyl-7 '-((9aR) -octahydro-2H-pyrazino [1,2-a] pyrazin-2-ylmethyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22' -[20] oxa [13] thia [1,14] diazacyclocyclo [14.7.2.0 ~ 3,6 ~ .0 ~ 19,24 ~] Pentacosa [16,18,24] triene] -15'-one 13 ', 13'-dioxide, (1S, 3'R, 6 'R, 7'S, 11'S, 12'R) -6-chloro-7'-hydroxy-11', 12'-dimethyl-7 '-((9aS) -octahydro-2H-pyrazino [1,2 -a] pyrazin-2-ylmethyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6--0.19-24]] Pentacosa [16,18,24] triene] -15'-on 13 ', 13'-dioxide (Example 479) (0.15 g, 0.199 mmol) and diisopropylethylamine (1.5 mL, 8.62 mmol) were added as a solid to the n-hydroxysuccinimide ester (0.303 g, 1.789 mmol) at room temperature as a solid. The resulting mixture was stirred at rt for 3 h. MeOH (8 mL) was added to the reaction mixture. The resulting mixture was stirred at rt for 20 min and then concentrated in vacuo. The crude residue was added directly onto silica gel precolumn (25 g) and separated by combi-flash column chromatography using 12 g ISCO gold column (eluting with 1% to 20% MeOH in DCM) 30 mg. A mixture of the crude products of was obtained, which was eluted with a preparative reversed phase HPLC (Gemini ™ Prep C18 10 μm column; Phenomenex, Torrance, CA; eluting with a gradient of 20% to 90% of MeCN in water, with both solvents Contains 0.1% TFA, separated by 15 minute gradient in a 24 minute method, and after freeze drying, 18.5 mg of methyl 3-((9aR) -8-(((1S, 3'R, 6'R, 7'R, 11'S, 12'R) -6-Chloro-7'-hydroxy-11 ', 12'-dimethyl-13', 13'-dioxido-15'-oxo-3,4-di Hydro-2H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6-0.0-19,24-] pentacosa [ 16,18,24] trien] -7'-yl) methyl) octahydro-2H-pyrazino [1,2-a] pyrazin-2-yl) propanoate and methyl 3-((9aR) -8 -(((1S, 3'R, 6 'R, 7'S, 11'S, 12'R) -6-chloro-7'-hydroxy-11', 12'-dimethyl-13 ', 13'-deoxido-15'-oxo-3,4- Dihydro-2H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6-0.0-19,24-] pentacosa [16,18,24] trien] -7'-yl) methyl) octahydro-2H-pyrazino [1,2-a] pyrazin-2-yl) propanoate and methyl 3-((9aS)- 8-(((1S, 3'R, 6'R, 7'R, 11'S, 12'R) -6-chloro-7'-hydroxy-11 ', 12'-dimethyl-13', 13 '-Dioxido-15'-oxo-3,4-dihydro-2H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0- 3,6 ~ .0 ~ 19,24 ~] pentacosa [16,18,24] trien] -7'-yl) methyl) octahydro-2H-pyrazino [1,2-a] pyrazine-2- 1) propanoate and methyl 3-((9aS) -8-((((1S, 3'R, 6'R, 7'S, 11'S, 12'R) -6-chloro-7'-hydroxy-11 ' , 12'-Dimethyl-13 ', 13'-dioxido-15'-oxo-3,4-dihydro-2H-spiro [naphthalene-1,22'-[20] oxa [13] thia [1 , 14] diazettracyclo [14.7 .2.0 ~ 3,6 ~ .0 ~ 19,24 ~] Pentacosa [16,18,24] trien] -7'-yl) methyl) octahydro-2H-pyrazino [1,2-a] pyrazine -2-yl) propanoate (Example 499) was obtained as an epimeric mixture in an approximately 1-to-1-to-1-to-1 ratio. MS (ESI, cation) m / z 841.0 (M + l) ⁺ . Further, (1S, 3'R, 6'R, 7'R, 11'S, 12'R) -7 '-(((9aR) -8-acryloyloctahydro-2H-pyrazino [1,2 -a] pyrazin-2-yl) methyl) -6-chloro-7'-hydroxy-11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1, 22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [16,18,24] triene]- 15'-one 13 ', 13'-dioxide; (1S, 3'R, 6'R, 7'R, 11'S, 12'R) -7 '-(((9aS) -8-acryloyloctahydro-2H-pyrazino [1,2-a] Pyrazin-2-yl) methyl) -6-chloro-7'-hydroxy-11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'- [20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [16,18,24] triene] -15'- On 13 ', 13'-dioxide; (1S, 3'R, 6'R, 7'S, 11'S, 12'R) -7 '-(((9aR) -8-acryloyloctahydro-2H-pyrazino [1,2-a] pyrazine- 2-yl) methyl) -6-chloro-7'-hydroxy-11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-[20 ] Oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [16,18,24] triene] -15'-one 13 ', 13'-dioxide; And (1S, 3'R, 6'R, 7'S, 11'S, 12'R) -7 '-(((9aS) -8-acryloyloctahydro-2H-pyrazino [1,2-a] pyrazine -2-yl) methyl) -6-chloro-7'-hydroxy-11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-[ 20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [16,18,24] triene] -15'-one 13 ', 13'-dioxide (Example 500) was isolated as a white solid that is an epimeric mixture in a 1-to-1-to-1-to-1 ratio. MS (ESI, cation) m / z 808.8 (M + l) ⁺ .

Example 507

(1S, 3'R, 6'R, 7'S, 11'S, 12'R) -7 '-(aminomethyl) -6-chloro-7'-hydroxy-11', 12'-dimethyl-3,4 -Dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazettracyclo [14.7.2.0-3,6-0.0-19, 24 ~] pentacosa [16,18,24] triene] -15'-on 13 ', 13'-dioxide or (1S, 3'R, 6'R, 7'S, 11'S, 12'R) -7' -(Aminomethyl) -6-chloro-7'-hydroxy-11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-[20] Oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [16,18,24] triene] -15'-one 13 ' , 13'-dioxide

(1S, 3'R, 6'R, 7'S, 11'S, 12'R) -7 '-(azidomethyl) -6-chloro-7'-hydroxy-11', 12'-dimethyl-3, 4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazettracyclo [14.7.2.0-3,6.0-19,24] Pentacosa [16,18,24] triene] -15'-on 13 ', 13'-dioxide or (1S, 3'R, 6'R, 7'R, 11'S, 12'R) -7'- (Azidomethyl) -6-chloro-7'-hydroxy-11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-[20] Oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6.0-19,24] pentacosa [16,18,24] triene] -15'-one 13 ', 13'- Dioxide (Example 506) (36.0 mg, 0.055 mmol) was dissolved in ethyl acetate (5.0 mL) and platinum (IV) oxide (2.49 mg, 11.0 μmol) was added. The reaction vessel was filled with nitrogen to 15 psi and stirred vigorously for 2.5 hours. MeOH (1.5 mL) was added and the reaction vessel was refilled with nitrogen (15 psi) and stirred overnight. The slurry was filtered and the precipitate was washed with DMSO to leave no product on the catalyst. The filtrate was concentrated. Crude by reverse phase preparative HPLC using Phenomenex Gemini column (10 μm, C18, 100 μs, 150 × 30 mm; CH ₃ CN / H ₂ O with 0.1% TFA, gradient from 20% to 85% over 30 minutes) Purification of (1S, 3'R, 6'R, 7'S, 11'S, 12'R) -7 '-(aminomethyl) -6-chloro-7'-hydroxy-11', 12'-dimethyl- 3,4-Dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6-0.0 ~ 19,24 ~] pentacosa [16,18,24] triene] -15'-one 13 ', 13'-dioxide or (1S, 3'R, 6'R, 7'S, 11'S, 12'R) -7 '-(aminomethyl) -6-chloro-7'-hydroxy-11', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'- [20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [16,18,24] triene] -15'- On 13 ', 13'-dioxide was obtained as a di-TFA salt (32 mg, 0.037 mmol, 68% yield). MS (ESI, cation) m / z 630.2 (M + H) ⁺ .

Examples 517 and 518

(1S, 3'R, 6'R, 7'R, 11'S, 12'R) -7'-ethoxy-7 '-((9aS) -hexahydropyrazino [2,1-c] [1, 4] oxazine-8 (1H) -ylmethyl) -12 '-(2-methoxyethyl) -11'-methyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [16,18,24] triene] -15 '-One 13', 13'-dioxide and (1S, 3'R, 6'R, 7'R, 11'S, 12'R) -6-chloro-7'-ethoxy-7 '-((9aS) Hexahydropyrazino [2,1-c] [1,4] oxazine-8 (1H) -ylmethyl) -12 '-(2-methoxyethyl) -11'-methyl-3,4-di Hydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~ ] Pentacosa [16,18,24] triene] -15'-on 13 ', 13'-dioxide

The reaction vessel was filled with platinum (IV) oxide (18.6 mg, 0.082 mmol), then placed in Biotage Endeavor (1S, 3'R, 6'R, 7'R, 8) in EtOAc (3 mL). 'E, 11'S, 12'R) -6-chloro-7'-ethoxy-7'-((9aS) -hexahydropyrazino [2,1-c] [1,4] oxazine-8 (1H ) -Ylmethyl) -12 '-(2-methoxyethyl) -11'-methyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-[20] oxa [13 ] Thia [1,14] diaza tetracyclo [14.7.2.0-3,6-0.0-19,24-] pentacosa [8,16,18,24] tetraene] -15'-one 13 ', Treated with 13'-dioxide (128 mg) solution. The vessel was purged three times with Ar, then pressurized with H ₂ to 200 psi and stirred at 80 ° C. for 20 hours (at 250 RPM). The vessel was cooled to room temperature, purged three times with Ar, and then filtered through a pad of celite rinsed thoroughly with EtOAc. The filtrate was concentrated in vacuo and purified by reverse phase preparative HPLC (Shimadzu) using Phenomenex Luna column (5 μm, C18, 110 mm 3, Axia, 150 mm × 21.2 mm) (MeCN (0.1% in water with 0.1% TFA)). Eluting at a rate of 30 mL / min over 20 minutes using a linear gradient of 25% to 100%). The desired fractions were poured into 10% Na ₂ CO ₃ and extracted with DCM (2 × 5 mL). The combined organic layers were dried over MgSO ₄ and concentrated in vacuo to afford (1S, 3'R, 6'R, 7'R, 11'S, 12'R) -6-chloro-7'-ethoxy-7 '-((9aS ) -Hexahydropyrazino [2,1-c] [1,4] oxazine-8 (1H) -ylmethyl) -12 '-(2-methoxyethyl) -11'-methyl-3,4- Dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazettracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] Pentacosa [16,18,24] triene] -15'-one 13 ', 13'-dioxide (Example 518) was obtained as a white solid (32.8 mg, 0.040 mmol, 13% yield). MS (ESI, cation) m / z 827.2 (M + H) ⁺ . Further, (1S, 3'R, 6'R, 7'R, 11'S, 12'R) -7'-ethoxy-7 '-((9aS) -hexahydropyrazino [2,1-c] [1,4] oxazine-8 (1H) -ylmethyl) -12 '-(2-methoxyethyl) -11'-methyl-3,4-dihydro-2H, 15'H-spiro [naphthalene- 1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [16,18,24] triene ] -15'-on 13 ', 13'-dioxide (Example 517) was isolated as a white eluting peak as an early eluting peak (12.9 mg, 0.016 mmol, 6% yield). MS (ESI, cation) m / z 793.3 (M + H) ⁺ .

Example 519

(1S, 3'R, 6'R, 7'R, 11'S, 12'R) -6-Chloro-7'-ethoxy-12 '-(2-methoxyethyl) -11'-methyl-7' -(((3R) -3-methyl-4- (2-propaneyl) -1-piperazinyl) methyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 ' -[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0 ~ 3,6 ~ .0 ~ 19,24 ~] pentacosa [16,18,24] triene] -15 ' -On 13 ', 13'-dioxide

Step 1: (1S, 3'R, 6'R, 7'R, 11'S, 12'R) -6-Chloro-7'-ethoxy-7 '-(hydroxymethyl) -12'-(2- Methoxyethyl) -11'-methyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatracyclo [ 14.7.2.0 ~ 3,6 ~ .0 ~ 19,24 ~] Pentacosa [16,18,24] triene] -15'-on 13 ', 13'-dioxide

The reaction vessel was charged with Pt (5 wt%, 54.2 mg, 0.295 mmol) in carbon and placed in a Biotage endeavor and (1S, 3'R, 6'R, 7'R, 8 ') in EtOAc (3.25 mL). E, 11'S, 12'R) -6-Chloro-7'-ethoxy-7 '-(hydroxymethyl) -12'-(2-methoxyethyl) -11'-methyl-3,4-dihydro -2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazettracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] Was treated with a solution of pentacosa [8,16,18,24] tetraen] -15'-one 13 ', 13'-dioxide (207 mg, 0.295 mmol) (the solution was (1S, 3'R, 6'). R, 8'E, 11'S, 12'R) -6-Chloro-12 '-(2-methoxyethyl) -11'-methyl-3,4-dihydro-2H, 7'H, 15'H- Spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6-0.0-19,24-] pentacosa [8,16, 18,24] tetraene] -7 ', 15'-dione 13', 13'-dioxide, obtained in a manner analogous to general method 3, steps 1-2. The vessel was purged three times with Ar, then pressurized with H ₂ to 200 psi and stirred at 80 ° C. for 20 hours (at 250 RPM). The vessel was cooled to room temperature, purged three times with Ar, and then filtered through a pad of celite rinsed thoroughly with EtOAc. The filtrate was concentrated in vacuo to (1S, 3'R, 6'R, 7'R, 11'S, 12'R) -6-chloro-7'-ethoxy-7 '-(hydroxymethyl) -12'- (2-methoxyethyl) -11'-methyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diaza Tetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [16,18,24] triene] -15'-one 13 ', 13'-dioxide was obtained as a white solid ( 196 mg, 0.279 mmol, 94% yield). MS (ESI, cation) m / z 703.3 (M + H) ⁺ .

Step 2: (1S, 3'R, 6'R, 7'R, 11'S, 12'R) -6-chloro-7'-ethoxy-12 '-(2-methoxyethyl) -11'-methyl -15'-oxo-3,4-dihydro-2H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diaza tetracyclo [14.7.2.0-3,6] .0 ~ 19,24 ~] Pentacosa [16,18,24] triene] -7'-carbaldehyde 13 ', 13'-dioxide

(1S, 3'R, 6'R, 7'R, 11'S, 12'R) -6-chloro-7'-ethoxy-7 '-(hydroxy) in DCM (10 mL), cooled in ice bath Methyl) -12 '-(2-methoxyethyl) -11'-methyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-[20] oxa [13] thia [ 1,14] diatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [16,18,24] triene] -15'-one 13 ', 13'-dioxide ( 161 mg, 0.229 mmol) was added dropwise 0.3 M des-martin periodinan (1.0 mL, 0.300 mmol) in DCM over 2 minutes. After 1.5 hours, about 60% of conversion was completed by liquid chromatography-mass spectrometry (LC-MS), and 0.9 mL of 0.3 M des-martin periodinan in DCM was added dropwise over 1 minute to treat the reaction. It was. After an additional 2.5 hours, the conversion is complete according to LC-MS. The reaction was treated with 5 mL of saturated sodium hydrogen sulfite and stirred for 20 minutes. The reaction was poured into water (15 mL) to separate the organic layer. The aqueous layer was extracted with DCM (1 × 5 mL). The combined organic layers were concentrated in vacuo and adsorbed onto a silica gel plug and chromatographically separated through a prefilled silica gel column of Redi-Sep® (gold, 12 g; eluting with 0% to 25% EtOAc in heptanes). (1S, 3'R, 6'R, 7'R, 11'S, 12'R) -6-Chloro-7'-ethoxy-12 '-(2-methoxyethyl) -11'-methyl-15' Oxo-3,4-dihydro-2H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diaza tetracyclo [14.7.2.0-3,6-0.0 ... 19,24-] pentacosa [16,18,24] triene] -7'-carbaldehyde 13 ', 13'-dioxide was obtained as a white solid (105 mg, 0.150 mmol, 65.4% yield). MS (ESI, cation) m / z 701.2 (M + H) ⁺ .

Step 3: (1S, 3'R, 6'R, 7'R, 11'S, 12'R) -6-Chloro-7'-ethoxy-12 '-(2-methoxyethyl) -11'-methyl -7 '-(((3R) -3-methyl-4- (2-propanyl) -1-piperazinyl) methyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1 , 22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [16,18,24] triene] -15'-on 13 ', 13'-dioxide

In a round bottom flask, (R) -1-isopropyl-2-methylpiperazine (68.2 mg, 0.285 mmol) with TFA salt and DCE (2 mL) (1S, 3'R, 6'R, 7'R, 11'S, 12'R) -6-Chloro-7'-ethoxy-12 '-(2-methoxyethyl) -11'-methyl-15'-oxo-3,4-dihydro-2H-spiro [naphthalene -1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [16,18,24] tree N] -7'-carbaldehyde 13 ', 13'-dioxide (50 mg, 0.071 mmol) and N, N-diisopropylethylamine (0.1 mL, 0.574 mmol) were charged. After 1.5 hours, the solution was treated with sodium triacetoxyborohydride (6 mg). After an additional 3 hours, the reaction was further treated with sodium triacetoxyborohydride (7 mg). After a further 16 hours, the reaction was again treated with sodium triacetoxyborohydride (6 mg). The reaction was monitored by LC-MS and sodium triacetoxyborohydride was added in 5-10 mg units until the reaction was judged complete. After an additional 24 hours, the reaction was diluted with DCE (3 mL). After 4 days, the reaction was treated with acetic acid (12 μL, 0.208 mmol). After an additional 24 hours, additional acetic acid (18 μL) was added. After an additional 24 hours, the reaction was further treated with 30 mg of amine. After an additional 96 hours, the reaction was treated with a higher amount of sodium triacetoxyborohydride to induce the reaction to be the desired product or alcohol resulting from reducing aldehyde. If no further progress was suggested by LC-MS, the reaction was quenched with water and the aqueous layer was extracted with DCM (2 × 10 mL). The combined DCM layers were concentrated in vacuo and adsorbed onto a silica gel plug and a redi-Sep® prefilled silica gel column (gold, 12 g; EtOAc: EtOH in heptane (3: 1) gradient from 0% to 80% (1S, 3'R, 6'R, 7'R, 11'S, 12'R) -6-chloro-7'-ethoxy-12 '-(2-meth). Methoxyethyl) -11'-methyl-7 '-(((3R) -3-methyl-4- (2-propaneyl) -1-piperazinyl) methyl) -3,4-dihydro-2H, 15 'H-spiro [naphthalene-1,22'-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6-0.0-19,24-] pentacosa [16 , 18,24] triene] -15'-one 13 ', 13'-dioxide was obtained as a white solid (24.2 mg, 0.029 mmol, 41.0% yield). MS (ESI, cation) m / z 827.4 (M + H) ⁺ .

Table 1 lists the compounds prepared by the general methods presented herein.

Example 100001

(1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7 '-(hydroxymethyl) -7'-methoxy-11', 12'-di Methyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diaza tetracyclo [14.7.2.0-3,6] .0 ~ 19,24 ~] Pentacosa [8,16,18,24] tetraene] -15'-one 13 ', 13'-dioxide

Step 1: (1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7 '-(1,3-dithiane-2-yl) -7 '-Hydroxy-11', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] dia Jatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ', 13'-dioxide and (1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7 '-(1,3-dithiane-2-yl) -7'-hydroxy-11', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0 ~ 3,6 ~ .0 ~ 19,24 ~] Pentacosa [8,16,18,24] tetraene] -15'-on 13 ', 13'-dioxide

To a 250 mL round bottom flask was added 1,3-dithiane (4.79 g, 39.8 mmol) and THF (100 mL). The mixture was cooled to −78 ° C. and n-butyllithium (1.6 M solution in hexanes, 22.5 mL, 36.1 mmol) was added over 8 minutes. The solution was stirred for 30 min in a bath at -78 ° C. In a separate 100 mL flask (1S, 3'R, 6'R, 8'E, 11'S, 12'R) -6-chloro-11 ', 12'-dimethyl-3,4-dihydro-2H, 7'H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~ ] Pentacosa [8,16,18,24] tetraene] -7 ', 15'-dione 13', 13'-dioxide and THF (5 mL) were added. To this was added a complex solution of lanthanum (III) chloride-bislithium chloride (0.6 M in THF, 60.1 mL, 36.1 mmol), which was stirred at room temperature for 5 minutes. The solution was then cooled to −78 ° C. and added to Ditian solution via cannula. After 2.5 hours at −78 ° C., the solution was treated with saturated NH ₄ Cl and water. The pH of the solution was adjusted to pH = 4 with aqueous 10% citric acid and aqueous NaHCO ₃ . The solution was extracted with EtOAc and the combined extracts were filtered through celite. The extract was washed with water and brine, dried (Na ₂ SO ₄ ) and concentrated to (1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7 '-(1,3-dithiane-2-yl) -7'-hydroxy-11', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraene -15'-one 13 ', 13'-dioxide and (1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-(1,3-di Thian-2-yl) -7'-hydroxy-11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-[20] oxa [13 ] Thia [1,14] diaza tetracyclo [14.7.2.0-3,6-0.0-19,24-] pentacosa [8,16,18,24] tetraene] -15'-one 13 ', A mixture of 13'-dioxide was obtained as a brown oil which was used directly to carry out the next step. MS (ESI, cation) m / z 717.5 (M + H) ⁺ .

Step 2: (1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7 '-(1,3-dithiane-2-yl) -7 '-Methoxy-11', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] dia Jatetracyclo [14.7.2.0-3,6-0.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ', 13'-dioxide and (1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7 '-(1,3-dithiane-2-yl) -7'-methoxy-11', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0 ~ 3,6 ~ .0 ~ 19,24 ~] Pentacosa [8,16,18,24] tetraene] -15'-on 13 ', 13'-dioxide

(1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7 '-(1,3-dithiane-2-yl)-in a separate vial 7'-hydroxy-11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-[20] oxa [13] thia [1,14] Diazatetracyclo [14.7.2.0-3,6-0.0-19,24-] Pentacosa [8,16,18,24] tetraene] -15'-one 13 ', 13'-dioxide and (1S , 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7 '-(1,3-ditian-2-yl) -7'-hydroxy-11' , 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0 ~ 3,6 ~ .0 ~ 19,24 ~] Pentacosa [8,16,18,24] tetraene] -15'-one 13 ', 13'-dioxide (6.81 g, 9.49 mmol) and THF (100 mL) was added. The mixture was cooled to 0 ° C. and potassium bis (trimethylsilyl) amide (1 M in THF, 38.0 mL, 38.0 mmol) was added over 10 minutes. The solution was stirred at 0 ° C. for 5 minutes before iodine methane (2.36 mL, 38.0 mmol) was added over 3 minutes. After 2.5 hours at 0 ° C., the solution was poured into saturated NH ₄ Cl and the pH was adjusted to 4 using 1 M citric acid. The solution was extracted with EtOAc and the combined extracts were washed with brine, dried (Na ₂ SO ₄ ) and concentrated on silica. Purification by silica gel chromatography (0% to 35% EtOAc in heptanes containing 0.3% AcOH), 330 g Redi-Sep Gold column) (1S, 3'R, 6'R, 7'R, 8'E) , 11'S, 12'R) -6-chloro-7 '-(1,3-dithiane-2-yl) -7'-methoxy-11', 12'-dimethyl-3,4-dihydro- 2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] penta Cosa [8,16,18,24] tetraene] -15'-one 13 ', 13'-dioxide (1.66 g, 2.27 mmol, 24% yield) MS (ESI, cation) m / z 731.5 (M + H ) ⁺ And (1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7 '-(1,3-dithia-2--2-)-7'- Methoxy-11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-[20] oxa [13] thia [1,14] diazate Cyclo [14.7.2.0 to 3,6 to .0 to 19,24 to] pentacosa [8,16,18,24] tetraen] -15'-one 13 ', 13'-dioxide (4.69 g, 6.41 mmol , 68% yield) was obtained MS (ESI, cation) m / z 731.5 (M + H) ⁺ .

Step 3: (1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-methoxy-11 ', 12'-dimethyl-15'-oxo -3,4-dihydro-2H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazettracyclo [14.7.2.0-3,6-0.0-19, 24 ~] pentacosa [8,16,18,24] tetraene] -7'-carbaldehyde 13 ', 13'-dioxide

In a 250 mL round bottom flask equipped with a reflux condenser (1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7 '-(1,3-dithiane -2-yl) -7'-methoxy-11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-[20] oxa [13] Thia [1,14] diaza tetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraen] -15'-one 13 ', 13 '-Dioxide (1.63 g, 2.23 mmol), acetonitrile (40 mL) and water (10 mL) were added. The mixture was heated to 50 ° C. and calcium carbonate (1.12 g, 11.1 mmol) and iodine methane (1.38 mL, 22.3 mmol) were added. After 23 hours at 50 ° C., the solution was poured into saturated NH ₄ Cl and water and extracted with EtOAc. The combined extracts were washed with brine and then dried (Na ₂ SO ₄ ) and concentrated on silica. Purified by silica gel chromatography (0-40% EtOAc in heptanes, both containing 0.3% AcOH, Silicycle HP 120 g column) (1S, 3'R, 6'R, 7'S, 8'E, 11'S) , 12'R) -6-chloro-7'-methoxy-11 ', 12'-dimethyl-15'-oxo-3,4-dihydro-2H-spiro [naphthalene-1,22'-[20 ] Oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraene] -7'- Carbaldehyde 13 ', 13'-dioxide was obtained as a white solid (1.34 g, 2.09 mmol, 94% yield). MS (ESI, cation) m / z 641.3 (M + H) ⁺ .

Step 4: (1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7 '-(hydroxymethyl) -7'-methoxy-11', 12 '-Dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-[20] oxa [13] thia [1,14] diaza tetracyclo [14.7.2.0-3] , 6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraene] -15'-on 13 ', 13'-dioxide

(1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-methoxy-11 ', 12 in MeOH (2 mL) and THF (0.5 mL) '-Dimethyl-15'-oxo-3,4-dihydro-2H-spiro [naphthalene-1,22'-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0 ~ 3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraene] -7'-carbaldehyde 13 ', 13'-dioxide (30 mg, 0.047 mmol) in room temperature solution Sodium borohydride (17 mg, 0.47 mmol) was added. After 5 minutes at room temperature, the solution was poured into saturated NaCl and extracted with EtOAc. The combined extracts were dried (Na ₂ SO ₄ ) and concentrated. Purified by silica gel chromatography (0% to 60% EtOAc in heptanes containing 0.3% AcOH) (4 g column) (1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12 '). R) -6-chloro-7 '-(hydroxymethyl) -7'-methoxy-11', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1, 22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraene ] -15'-one 13 ', 13'-dioxide was obtained as a white solid (10 mg, 0.016 mmol, 50% yield). ¹ H NMR (400 MHz, Chloroform-d) δ 7.95-8.01 (m, 1H), 7.68 (d, J = 8.61 Hz, 1H), 7.16-7.20 (m, 1H), 7.10 (dd, J = 1.86, 13.99 Hz, 2H), 6.85-6.95 (m, 2H), 5.71-5.80 (m, 1H), 5.67 (d, J = 0.98 Hz, 1H), 4.29-4.41 (m, 1H), 4.07 (d, J = 4.89 Hz, 3H), 3.87-3.97 (m, 2H), 3.72 (br d, J = 14.48 Hz, 1H), 3.26 (d, J = 14.28 Hz, 1H), 3.10 (s, 3H), 2.96- 3.04 (m, 1H), 2.72-2.80 (m, 2H), 2.56-2.65 (m, 1H), 2.44 (s, 1H), 1.75-2.28 (m, 9H), 1.55-1.71 (m, 1H), 1.50 (d, J = 7.04 Hz, 3H), 1.50-1.41 (m, 1H), 1.06 (d, J = 6.85 Hz, 3H). Exchangeable protons were not observed. MS (ESI, cation) m / z 643.2 (M + H) ⁺ .

Example 100002

2-((1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-methoxy-11 ', 12'-dimethyl-13', 13 '-Dioxido-15'-oxo-3,4-dihydro-2H-spiro [naphthalene-1,22'-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0 ~ 3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraen] -7'-yl) -N, N-dimethylacetamide

((1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-methoxy-11 ', 12'-dimethyl-13', 13'- Dioxido-15'-oxo-3,4-dihydro-2H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diaza tetracyclo [14.7.2.0-3] , 6 ~ .0 ~ 19,24 ~] Pentacosa [8,16,18,24] tetraen] -7'-yl) acetic acid (60 mg, 0.089 mmol) was dissolved in THF (1.8 mL) and lithium hydroxide (2.0 M in water, 0.18 mL, 0.36 mmol) was added. The mixture was stirred at room temperature for 10 minutes and then concentrated in vacuo to yield the starting material lithium carboxylate as an off-white solid and used for these amide bonds. The lithium carboxylate suspension prepared in advance and suspended in N , N -dimethylformamide (1.8 mL) was stirred, followed by HATU (51.0 mg, 0.134 mmol) and dimethylamine (2.0 M in THF, 0.134 mL, 0.268 mmol). Added. The reaction mixture was stirred at rt for 10 min. The reaction mixture was diluted with water and EtOAc and transferred to a separatory funnel. 1.0 M HCl was added and the phases were mixed. The organic layer was separated, washed sequentially with 1.0 M LiCl and brine, dried over magnesium sulfate and concentrated under reduced pressure. Purification via silica gel flash chromatography (using EtOAc in heptane (containing 0.3% AcOH) in a gradient of 50% to 100%) 2-((1S, 3'R, 6'R, 7'S, 8'E, 11'S) , 12'R) -6-Chloro-7'-methoxy-11 ', 12'-dimethyl-13', 13'-dioxido-15'-oxo-3,4-dihydro-2H-spiro [Naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ 0.19 ~ 24,24] pentacosa [8,16,18 , 24] tetraen] -7'-yl) -N, N-dimethylacetamide was obtained as a white solid (38 mg, 0.054 mmol, 61% yield). ¹ H NMR (300 MHz, Chloroform- d ) δ ppm 7.71 (d, J = 8.48 Hz, 1H) 7.17 (dd, J = 8.77, 2.19 Hz, 1H) 7.07-7.11 (m, 1H) 7.01- 7.04 (m, 1H) 6.95-7.00 (m, 1H) 6.88-6.93 (m, 1H) 5.71-5.92 (m, 2H) 4.00-4.11 (m, 3H) 3.84 (br d, J = 15.20 Hz, 1 H) 3.70 (br d, J = 14.03 Hz, 1 H) 3.30 (d, J = 14.32 Hz, 1 H) 3.17 (s, 3 H) 3.08-3.15 (m, 2 H) 3.06 (s , 3 H) 3.01 (s, 1 H) 2.94 (s, 3 H) 2.65-2.87 (m, 3 H) 2.39-2.65 (m, 3 H) 2.02-2.21 (m, 4 H) 1.51-1.97 (m , 11 H) 1.30-1.47 (m, 5H) 1.05 (d, J = 6.14 Hz, 3H). MS (ESI, + ve) m / z 666.2 [M−OMe] ⁺ .

Example 100003

(1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-methoxy-11 ', 12'-dimethyl-7'-(2-pyri Diyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6] .0 ~ 19,24 ~] Pentacosa [8,16,18,24] tetraene] -15'-one 13 ', 13'-dioxide

Step 1: (1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-11 ', 12'-dimethyl-7' -(2-pyridinyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatracyclo [14.7. 2.0 to 3,6 to 0 to 19,24 to pentacosa [8,16,18,24] tetraen] -15'-one 13 ', 13'-dioxide and (1S, 3'R, 6' R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-11 ', 12'-dimethyl-7'-(2-pyridinyl) -3,4-dihydro -2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] Pentacosa [8,16,18,24] tetraene] -15'-on 13 ', 13'-dioxide

A 2-bromopyridine (105 μL, 1.1 mmol) solution in THF (4 mL) was cooled to −78 ° C. under nitrogen atmosphere. A solution of n-butyllithium (2.5 M, 422 μL, 1.1 mmol) in hexanes was added dropwise and the reaction mixture was stirred for 30 minutes. (1S, 3'R, 6'R, 8'E, 11'S, 12'R) -6-chloro-11 ', 12'-dimethyl-3,4-dihydro-2H, in THF (1 mL), 7'H, 15'H-spiro [naphthalene-1,22 '[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] A solution of pentacosa [8,16,18,24] tetraene] -7 ', 15'-dione 13', 13'-dioxide (300 mg, 0.5 mmol) was added dropwise and the reaction mixture was allowed to warm to room temperature overnight. . Aqueous saturated NH ₄ Cl solution was added and the reaction mixture was extracted with EtOAc. The organic phase was separated, washed with brine and concentrated under reduced pressure. Purify the yellow solid by column chromatography using silica gel (eluted with EtOAc in hexanes (containing 0.3% HOAc) in a gradient of 0% to 35%) (1S, 3'R, 6'R, 7 '). R, 8'E, 11'S, 12'R) -6-Chloro-7'-hydroxy-11 ', 12'-dimethyl-7'-(2-pyridinyl) -3,4-dihydro-2H , 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6-0.0-19,24-] pentacosa [8,16,18,24] tetraene] -15'-on 13 ', 13'-dioxide and (1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6 -Chloro-7'-hydroxy-11 ', 12'-dimethyl-7'-(2-pyridinyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'- [20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraene] -15 A mixture of '-on 13', 13'-dioxide was obtained as a light yellow solid (129 mg). The mixture was used for next step without further purification. MS (ESI, cation) m / z 676.0 (M + H) ⁺ .

Step 2: (1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-methoxy-11 ', 12'-dimethyl-7'-( 2-pyridinyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '[20] oxa [13] thia [1,14] diaza tetracyclo [14.7.2.0-3] , 6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraene] -15'-on 13 ', 13'-dioxide

(1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-11 ', 12'-dimethyl-7'-(2 -Pyridinyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diaza tetracyclo [14.7.2.0-3] , 6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraene] -15'-one 13 ', 13'-dioxide and (1S, 3'R, 6'R, 7'S , 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-11 ', 12'-dimethyl-7'-(2-pyridinyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6-0.0-19,24-] pentacosa [ A mixture of 8,16,18,24] tetraen] -15'-on 13 ', 13'-dioxide (129 mg, 0.19 mmol) was dissolved in THF (5 mL) and the solution was cooled using a water bath. Sodium hydride (60% dispersion in mineral oil, 201 mg, 5 mmol) was added in one portion. After 15 minutes, iodine methane (624 μL, 10 mmol) was added. After 2 hours, the addition of each of NaH and MeI was added once more. Aqueous saturated NH ₄ Cl solution was added and the reaction mixture was extracted with EtOAc. The solvent was removed under reduced pressure. Concentrate the solution by preparative reverse phase HPLC using a Phenomenex Gemini column (10 μm, C18, 110 μs, 100 × 50 mm; eluting CH3CN in H2O with 0.1% TFA over a 20 minute gradient to 10% to 100%). Purified to obtain 21 mg of [(1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-methoxy-11 ', 12'-dimethyl-7 '-(2-pyridinyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-[20] oxa [13] thia [1,14] diazettracyclo [14.7 .2.0-3,6-0.0-19,24-] Pentacosa [8,16,18,24] tetraene] -15'-on 13 ', 13'-dioxide (the second eluting peak) Obtained as a white solid. ¹ H NMR (400 MHz, Chloroform- d ) δ ppm 1.15 (m, 3 H) 1.24-1.34 (m, 2 H) 1.48 (m, 3 H) 1.61-1.80 (m, 2 H) 1.83-1.93 (m , 2 H) 1.95-2.07 (m, 3 H) 2.19-2.32 (m, 3 H) 2.62-2.82 (m, 5 H) 3.06 (s, 3 H) 3.11-3.21 (m, 2 H) 3.70 (m , 1 H) 3.96-4.01 (m, 1 H) 4.04-4.09 (m, 1 H) 4.17 (m, 1 H) 5.86-6.02 (m, 2 H) 6.92-6.97 (m, 1 H) 6.99-7.03 (m, 1H) 7.09 (d, J = 8.02 Hz, 2H) 7.18 (dd, J = 8.41, 1.96 Hz, 1H) 7.65-7.71 (m, 2H) 8.34-8.40 (m, 2H) 9.02 (d, J = 5.09 Hz, 1 H). MS (ESI, cation) m / z 690.0 (M + H) ⁺ .

Example 100004

(1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-methoxy-11 ', 12'-dimethyl-7'-(3-pyrid Dazinyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3, 6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraene] -15'-on 13 ', 13'-dioxide

Step 1: (1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-11 ', 12'-dimethyl-7'-( 3-pyridazinyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0 ~ 3,6 ~ .0 ~ 19,24 ~] Pentacosa [8,16,18,24] tetraene] -15'-on 13 ', 13'-dioxide

N-butyllithium (2.5 M in THF, 2.4 mL, 6.0 mmol) in a solution of 2,2,6,6-tetramethylpiperidine (1.06 mL, 6.3 mmol) in THF (28 mL) cooled to 0 ° C. The solution was added under nitrogen atmosphere. The reaction was stirred at 0 ° C for 25 minutes and then cooled to -78 ° C. A solution of pyridazine (110 μL, 1.5 mmol) in THF (5 mL) was added dropwise followed by (1S, 3'R, 6'R, 8'E, 11'S, 12'R) -6 in THF (3 mL). -Chloro-11 ', 12'-dimethyl-3,4-dihydro-2H, 7'H, 15'H-spiro [naphthalene-1,22' [20] oxa [13] thia [1,14] Diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] Pentacosa [8,16,18,24] tetraene] -7 ', 15'-dione 13', 13'- Dioxide (300 mg, 0.502 mmol) solution was added dropwise. The reaction mixture was stirred at −78 ° C. for 2 hours and quenched by addition of aqueous saturated ammonium chloride solution. The reaction mixture was extracted with EtOAc. The organic phase was separated, washed with brine and concentrated under reduced pressure to afford crude. Purify the crude by silica gel chromatography (using EtOAc in heptane (containing 0.3% AcOH) in a gradient of 50% to 100%) to 106 mg (1S, 3'R, 6'R, 7'S, 8'E). , 11'S, 12'R) -6-chloro-7'-hydroxy-11 ', 12'-dimethyl-7'-(3-pyridazinyl) -3,4-dihydro-2H, 15'H Spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6-0.0-19,24-] pentacosa [8,16 , 18,24] tetraen] -15'-one 13 ', 13'-dioxide (second eluting peak). MS (ESI, cation) m / z 677.0 (M + H) ⁺ .

Step 2: (1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-methoxy-11 ', 12'-dimethyl-7'-( 3-pyridazinyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0 ~ 3,6 ~ .0 ~ 19,24 ~] Pentacosa [8,16,18,24] tetraene] -15'-on 13 ', 13'-dioxide

(1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-11 ', 12'-dimethyl in tetrahydrofuran (6.7 mL) -7 '-(3-pyridazinyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-[20] oxa [13] thia [1,14] diazate Cyclo [14.7.2.0-3,6 ~ .0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ', 13'-dioxide (137 mg, 0.2 mmol To the solution was added sodium hydride (60% dispersion in mineral oil, 81 mg, 2.0 mmol) in one portion. After 5 minutes, iomethane (251 μL, 4.1 mmol) was added and the reaction stirred for 2 hours. MeOH (3 mL) is added, eluting a Phenomenex Gemini column (10 μm, C18, 110 mm 3, 100 × 50 mm; CH 3 CN in H 2 O (containing 0.1% TFA) over 10 minutes with a gradient of 10% to 100% The reaction mixture was purified by preparative reversed phase HPLC using). Combine desired fractions and remove solvent under reduced pressure to afford 92 mg (1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-methoxy-11 ' , 12'-dimethyl-7 '-(3-pyridazinyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-[20] oxa [13] thia [1 , 14] diaza tetracyclo [14.7.2.0-3,6-0.0-19,24-] pentacosa [8,16,18,24] tetraene] -15'-one 13 ', 13'-dioxide Was obtained as a tan solid. ¹ H NMR (400 MHz, Chloroform- d ) δ ppm 1.03 (d, J = 6.06 Hz, 3H) 1.35 (d, J = 6.65 Hz, 3H) 1.72-1.87 (m, 2H) 1.89-2.23 ( m, 9 H) 2.73-2.84 (m, 3 H) 2.94-3.06 (m, 2 H) 3.11 (s, 3 H) 3.26 (d, J = 14.48 Hz, 1 H) 3.68 (d, J = 7.04 Hz , 1 H) 3.75 (d, J = 14.48 Hz, 1 H) 4.04-4.14 (m, 2 H) 4.32 (d, J = 15.06 Hz, 1 H) 5.43 (br.s., 9 H) 5.91 (d , J = 16.24 Hz, 1 H) 6.85-6.92 (m, 2 H) 7.03 (s, 1 H) 7.09 (s, 1 H) 7.16-7.21 (m, 1 H) 7.18 (d, J = 8.61 Hz, 1 H) 7.70 (d, J = 8.41 Hz, 1 H) 8.18 (br. S., 2 H) 9.48 (br. S., 1 H). MS (ESI, cation) m / z 691.0 (M + H) ⁺ .

Example 100005

2-((1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-methoxy-11 ', 12'-dimethyl-13', 13 '-Dioxido-15'-oxo-3,4-dihydro-2H-spiro [naphthalene-1,22'-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0 ~ 3,6 ~ 0.0 ~ 19,24 ~] penta Kosa [8,16,18,24] tetraene; -7'- yl) - N - (2- methoxyethyl) - N - methylacetamide

Step 1: 2-methyl-2-propanyl ((1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-11 ', 12 '-Dimethyl-13', 13'-dioxido-15'-oxo-3,4-dihydro-2H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14 ] Diazatetracyclo [14.7.2.0-3,6-0.0-19,24-] pentacosa [8,16,18,24] tetraen] -7'-yl) acetate and 2-methyl-2- Propanyl ((1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-11 ', 12'-dimethyl-13' , 13'-dioxido-15'-oxo-3,4-dihydro-2H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazettracyclo [14.7 .2.0 ~ 3,6 ~ .0 ~ 19,24 ~] Pentacosa [8,16,18,24] tetraene] -7'-yl) acetate

(1S, 3'R, 6'R, 8'E, 11'S, 12'R) -6-chloro-11 ', 12'-dimethyl-3,4-dihydro- in tetrahydrofuran (50 mL) 2H, 7'H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazettracyclo [14.7.2.0-3,6-0.0-19, 24- ~] pentacosa [8,16,18,24] tetraene] -7 ', 15'-dione 13', 13'-dioxide (2.90 g, 4.86 mmol) in a solution of 2-tert-butoxy-2 Oxoethyl zinc chloride (0.5 M in diethyl ether, 48.6 mL, 24.28 mmol) was added under a nitrogen atmosphere. The reaction mixture was stirred at rt for 1 h. The reaction mixture was quenched with saturated aqueous NH ₄ Cl (150 mL) and extracted with EtOAc (100 mL). The organic layer was separated, washed with saturated aqueous NH ₄ Cl: 30% aqueous NH ₄ OH (200 mL; 9: 1 ratio), washed with brine (100 mL), dried over MgSO ₄ , filtered, and vacuum Concentrated in 2-methyl-2-propanyl ((1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-11 ', 12 '-Dimethyl-13', 13'-dioxido-15'-oxo-3,4-dihydro-2H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14 ] Diazatetracyclo [14.7.2.0 ~ 3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraen] -7'-yl) acetate and 2-methyl-2- Propanyl ((1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-11 ', 12'-dimethyl-13' , 13'-dioxido-15'-oxo-3,4-dihydro-2H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazettracyclo [14.7 .2.0-3,6 ~ .0 ~ 19,24 ~] Pentacosa [8,16,18,24] tetraen] -7'-yl) acetate obtained a crude mixture of toluene and azeotrope twice It was used directly in the next step. MS (ESI, + ve) m / z 713.3 [M + H] ⁺ .

Step 2: (1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-7 '-(2-hydroxyethyl) -11' , 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0 ~ 3,6 ~ .0 ~ 19,24 ~] Pentacosa [8,16,18,24] tetraene] -15'-one 13 ', 13'-dioxide and (1S, 3'R, 6'R , 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-7 '-(2-hydroxyethyl) -11', 12'-dimethyl-3,4- Dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazettracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 Pentacosa [8,16,18,24] tetraene] -15'-on 13 ', 13'-dioxide

2-methyl-2-propanyl ((1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy in tetrahydrofuran (25 mL) -11 ', 12'-dimethyl-13', 13'-dioxido-15'-oxo-3,4-dihydro-2H-spiro [naphthalene-1,22 '-[20] oxa [13] Thia [1,14] diazatetracyclo [14.7.2.0-3,6-0.0-19,24-] pentacosa [8,16,18,24] tetraen] -7'-yl) acetate and 2 -Methyl-2-propanyl ((1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-11 ', 12'- Dimethyl-13 ', 13'-dioxido-15'-oxo-3,4-dihydro-2H-spiro [naphthalene-1,22'-[20] oxa [13] thia [1,14] dia Zirtracyclo [14.7.2.0 ~ 3,6 ~ .0 ~ 19,24 ~] Pentacosa [8,16,18,24] tetraen] -7'-yl) acetate in a stirred solution of a crude mixture of acetate Hydride (2.0 M solution in tetrahydrofuran, 10.41 mL, 20.82 mmol) was added under nitrogen atmosphere. The reaction mixture was stirred at rt for 16 h. Lithium borohydride (2.0 M solution in tetrahydrofuran, 5.21 mL, 10.4 mmol) was further added, followed by dropwise addition of methanol (1.69 mL, 41.6 mmol). The reaction mixture was stirred at rt for 24 h. Methanol (1.687 mL, 41.6 mmol) was further added and the reaction mixture was further stirred for 2.5 h. The reaction mixture was slowly quenched with saturated aqueous NH ₄ Cl (75 mL) and extracted twice with EtOAc (75 mL). The combined organic layers were separated, washed with brine (60 mL), dried over MgSO ₄ , filtered and concentrated in vacuo. The residue was purified by chromatography (silica gel; 0% to 10% MeOH in DCM) to (1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro- 7'-hydroxy-7 '-(2-hydroxyethyl) -11', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20 ] Oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraene] -15'- On 13 ', 13'-dioxide and (1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-7'-(2 -Hydroxyethyl) -11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-[20] oxa [13] thia [1,14] A mixture of diazatetracyclo [14.7.2.0-3,6-0.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ', 13'-dioxide Obtained as a white solid (2.58 g, 4.01 mmol, 96% yield). MS (ESI, + ve) m / z 643.2 [M + H] ⁺ .

Step 3: (1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7 '-(2-((dimethyl (2-methyl-2-propanyl ) Silyl) oxy) ethyl) -7'-hydroxy-11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-[20] oxa [ 13] thia [1,14] diatetracyclo [14.7.2.0-3,6-0.0-19,24-] pentacosa [8,16,18,24] tetraene] -15'-one 13 ' , 13'-dioxide

(1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-7 '-(2-hydroxy) in dichloromethane (50 mL) Ethyl) -11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-[20] oxa [13] thia [1,14] diazate Cyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraene] -15'-one 13 ', 13'-dioxide and (1S, 3' R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-7 '-(2-hydroxyethyl) -11', 12'-dimethyl -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6]. 0-19,24-] pentacosa [8,16,18,24] tetraene] -15'-on imidazole (1.274 g) in a stirred mixture of 13 ', 13'-dioxide (3.01 g, 4.68 mmol) , 18.72 mmol) and tert-butyldimethylsilyl chloride (1.41 g, 9.36 mmol) were added. The reaction mixture was stirred at rt for 72 h. Further tert-butyldimethylsilyl chloride (1.41 g, 9.36 mmol) and imidazole (1.274 g, 18.72 mmol) were added and the reaction mixture was further stirred at rt for 4 h. The reagent was added several more times while stirring the reaction mixture at room temperature until no further reaction was seen due to the addition. The reaction mixture was quenched with saturated aqueous NH ₄ Cl (125 mL) and extracted with DCM (75 mL). The organic layer was separated, dried over MgSO ₄ , filtered and concentrated in vacuo. The resulting residue was subjected to the original reaction conditions again and then stirred at room temperature for 2 hours. The reaction mixture was quenched with saturated aqueous NH ₄ Cl (125 mL) and extracted with DCM (75 mL). The organic layer was separated, dried over MgSO ₄ , filtered and concentrated in vacuo. The residue was purified by chromatography (silica gel; 0% to 50% EtOAc in heptanes) to (1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro- 7 '-(2-((dimethyl (2-methyl-2-propanyl) silyl) oxy) ethyl) -7'-hydroxy-11', 12'-dimethyl-3,4-dihydro-2H , 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6-0.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-on 13 ', 13'-dioxide (which is the second diastereomer eluting from the column) was obtained as a white solid (453 mg, 0.598 mmol, 13 % Yield). ¹ H NMR (400 MHz, Chloroform- d ) δ ppm 7.99 (1 H, s) 7.69 (1 H, d, J = 8.41 Hz) 7.18 (1 H, dd, J = 8.51, 2.25 Hz) 7.09 (1 H , d, J = 2.15 Hz) 6.92-6.96 (3 H, m) 5.71-5.78 (1 H, m) 5.59 (1 H, d, J = 16.04 Hz) 4.55 (1 H, br.s.) 3.96- 4.19 (5 H, m) 3.67-3.82 (2 H, m) 3.25 (1 H, d, J = 14.28 Hz) 3.02 (1 H, dd, J = 15.16, 10.27 Hz) 2.68-2.86 (2 H, m ) 2.35-2.47 (1 H, m) 2.26-2.36 (1 H, m) 2.12-2.24 (3 H, m) 1.77-2.08 (6 H, m) 1.65-1.77 (1 H, m) 1.51-1.62 ( 1 H, m) 1.46 (3 H, d, J = 7.04 Hz) 1.36-1.45 (1 H, m) 1.25-1.32 (1 H, m) 1.07 (3 H, d, J = 6.06 Hz) 0.91 (9 H, s) 0.10 (6H, d, J = 3.33 Hz). MS (ESI, + ve) m / z 757.2 [M + H] ⁺ .

Step 4: (1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7 '-(2-((dimethyl (2-methyl-2-propanyl ) Silyl) oxy) ethyl) -7'-methoxy-11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-[20] oxa [ 13] thia [1,14] diatetracyclo [14.7.2.0-3,6-0.0-19,24-] pentacosa [8,16,18,24] tetraene] -15'-one 13 ' , 13'-dioxide

(1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7 '-(2-((dimethyl (2-methyl) in tetrahydrofuran (2 mL) -2-propanyl) silyl) oxy) ethyl) -7'-hydroxy-11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'- [20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraene] -15 To a stirred solution of '-on 13', 13'-dioxide (225 mg, 0.297 mmol) and iodine methane (0.185 mL, 2.97 mmol) was added sodium hydride (60% dispersion in mineral oil, 119 mg, 2.97 mmol). The reaction mixture was stirred at rt for 17 h. The reaction mixture was quenched with saturated aqueous NH ₄ Cl (50 mL) and extracted with EtOAc (70 mL). The organic layer was separated, washed with brine (50 mL), dried over MgSO 4, filtered and concentrated in vacuo to afford the crude product (1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R). ) -6-chloro-7 '-(2-((dimethyl (2-methyl-2-propanyl) silyl) oxy) ethyl) -7'-methoxy-11', 12'-dimethyl-3, 4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19 , 24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ', 13'-dioxide was obtained and used directly in the next step. MS (ESI, + ve) m / z 793.3 [M + Na] ⁺ .

Step 5: (1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-Chloro-7 '-(2-hydroxyethyl) -7'-methoxy-11' , 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0 ~ 3,6 ~ .0 ~ 19,24 ~] Pentacosa [8,16,18,24] tetraene] -15'-on 13 ', 13'-dioxide

(1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7 '-(2-((dimethyl (2-methyl) in tetrahydrofuran (1.5 mL) -2-propanyl) silyl) oxy) ethyl) -7'-methoxy-11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'- [20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraene] -15 To a stirred solution of '-on 13', 13'-dioxide (229 mg, 0.297 mmol) was added tetrabutylammonium fluoride (1.0 M solution in tetrahydrofuran, 0.356 mL, 0.356 mmol). The reaction mixture was stirred at rt for 3.5 h. Tetrabutylammonium fluoride (1.0 M solution in tetrahydrofuran, 0.356 mL, 0.356 mmol) was further added and the reaction mixture was further stirred for 3 hours. The reaction mixture was concentrated. The residue was purified by chromatography (0% to 100% EtOAc in 0.3% AcOH in heptane) (1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6 -Chloro-7 '-(hydroxymethyl) -7'-methoxy-11', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[ 20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraen] -15 ' -On 13 ', 13'-dioxide was obtained as a white solid (178 mg, 0.271 mmol, 91% yield). ¹ H NMR (400 MHz, Chloroform- d ) δ ppm 8.10 (1 H, s) 7.68 (1 H, d, J = 8.61 Hz) 7.18 (1 H, dd, J = 8.51, 2.25 Hz) 7.09 (1 H , d, J = 2.15 Hz) 6.88-6.96 (3 H, m) 5.75-5.83 (1 H, m) 5.64 (1 H, d, J = 16.24 Hz) 4.29-4.37 (1 H, m) 4.02-4.15 (2 H, m) 3.91-3.99 (1 H, m) 3.80-3.88 (2 H, m) 3.72 (1 H, d, J = 14.28 Hz) 3.25 (1 H, d, J = 14.28 Hz) 3.11 ( 3 H, s) 3.02 (1 H, dd, J = 14.96, 10.66 Hz) 2.69-2.85 (2 H, m) 2.59 (1 H, q, J = 9.06 Hz) 2.34-2.47 (2 H, m) 2.12 -2.24 (2 H, m) 1.76-2.06 (8 H, m) 1.58-1.67 (1 H, m) 1.50 (3 H, d, J = 7.04 Hz) 1.38 (1 H, t, J = 12.91 Hz) 1.06 (3H, doublet, J = 6.85 Hz). MS (ESI, + ve) m / z 657.2 [M + H] ⁺ .

Step 6: ((1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-methoxy-11 ', 12'-dimethyl-13', 13'-dioxido-15'-oxo-3,4-dihydro-2H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazettracyclo [14.7. 2.0 ~ 3,6 ~ .0 ~ 19,24 ~] Pentacosa [8,16,18,24] tetraene] -7'-yl) acetaldehyde

(1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7 '-(2-hydroxyethyl) -7'- in dichloromethane (1 mL) Methoxy-11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-[20] oxa [13] thia [1,14] diazate Cyclo [14.7.2.0-3,6 ~ .0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ', 13'-dioxide (87 mg, 0.13 mmol ) And a stirred mixture of sodium bicarbonate (111 mg, 1.32 mmol) was added Dess-Martin periodinan (67.4 mg, 0.159 mmol). The reaction mixture was stirred at rt for 45 min. The reaction mixture was quenched with saturated aqueous NaHCO ₃ (25 mL) and extracted with EtOAc (30 mL). The organic layer was separated, washed with 1 M aqueous Na ₂ S ₂ O ₃ (20 mL), washed with brine (20 mL), dried over MgSO ₄ , filtered and concentrated in vacuo to afford the crude product ((1S , 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-methoxy-11 ', 12'-dimethyl-13', 13'-dioxido -15'-oxo-3,4-dihydro-2H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diaza tetracyclo [14.7.2.0-3,6] .0-19,24-] pentacosa [8,16,18,24] tetraen] -7'-yl) acetaldehyde was obtained and used directly in the next step.

Step 7: ((1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-methoxy-11 ', 12'-dimethyl-13', 13'-dioxido-15'-oxo-3,4-dihydro-2H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazettracyclo [14.7. 2.0 ~ 3,6 ~ .0 ~ 19,24 ~] Pentacosa [8,16,18,24] tetraen] -7'-yl) acetic acid

((1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-methoxy-11 ', 12'-di in tert-butanol (2 mL) Methyl-13 ', 13'-dioxido-15'-oxo-3,4-dihydro-2H-spiro [naphthalene-1,22'-[20] oxa [13] thia [1,14] diaza Tetracyclo [14.7.2.0-3,6-0.0-19,24-] pentacosa [8,16,18,24] tetraen] -7'-yl) acetaldehyde (174 mg, 0.266 mmol) and 2 To a stirred mixture of -methyl-2-butene (1.407 mL, 13.28 mmol) was added a solution of monobasic potassium phosphate (361 mg, 2.66 mmol) and sodium chloride (240 mg, 2.66 mmol) in water (2 mL). The reaction mixture was stirred at rt for 45 min. The reaction mixture is diluted with EtOAc (50 mL), washed with 1 M aqueous HCl (40 mL), washed with 1 M Na ₂ S ₂ O ₃ (40 mL), washed with brine (40 mL), MgSO Dried to ₄ , filtered and concentrated in vacuo. The residue was purified by chromatography (silica gel; 0% to 100% EtOAc in heptanes containing 0.3% AcOH) ((1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12 '). R) -6-chloro-7'-methoxy-11 ', 12'-dimethyl-13', 13'-dioxido-15'-oxo-3,4-dihydro-2H-spiro [naphthalene- 1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] Tetraene] -7'-yl) acetic acid was obtained as a white solid (142 mg, 0.212 mmol, 80% yield). ¹ H NMR (400 MHz, Chloroform- d ) δ ppm 8.11 (1 H, s) 7.68 (1 H, d, J = 8.41 Hz) 7.17 (1 H, d, J = 8.41 Hz) 7.08 (1 H, s ) 6.87-6.95 (3 H, m) 5.80-5.90 (1 H, m) 5.72 (1 H, d, J = 15.85 Hz) 4.36 (1 H, q, J = 7.17 Hz) 4.07 (2 H, s) 3.99 (1 H, d, J = 15.65 Hz) 3.71 (1 H, d, J = 14.48 Hz) 3.16-3.27 (5 H, m) 3.01 (1 H, dd, J = 15.55, 10.86 Hz) 2.71-2.84 (3 H, m) 2.66 (1 H, q, J = 9.00 Hz) 2.42 (1 H, quin, J = 9.15 Hz) 2.12-2.26 (2 H, m) 2.01-2.09 (1 H, m) 1.83- 2.01 (5 H, m) 1.79 (1 H, d, J = 7.24 Hz) 1.57-1.69 (1 H, m) 1.51 (3 H, d, J = 7.04 Hz) 1.35 (1 H, t, J = 13.11 Hz) 1.06 (3H, d, J = 6.65 Hz). MS (ESI, + ve) m / z 671.2 [M + H] ⁺ .

Step 8: 2-((1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-methoxy-11 ', 12'-dimethyl-13 ', 13'-dioxido-15'-oxo-3,4-dihydro-2H-spiro [naphthalene-1,22'-[20] oxa [13] thia [1,14] diazettracyclo [ 14.7.2.0 ~ 3,6 ~ .0 ~ 19,24 ~ ] penta Kosa [8,16,18,24] tetraene; -7'- yl) - N - (2- methoxyethyl) - N - methyl Acetamide

((1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-methoxy-11 ', 12'-dimethyl-13', 13'- Dioxido-15'-oxo-3,4-dihydro-2H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diaza tetracyclo [14.7.2.0-3] , 6 ~ .0 ~ 19,24 ~] Pentacosa [8,16,18,24] tetraen] -7'-yl) acetic acid (28 mg, 0.042 mmol) was dissolved in THF (0.5 mL) and lithium hydroxide (2.0 M in water, 0.083 mL, 0.17 mmol) was added. The mixture was stirred at room temperature for 10 minutes and then concentrated in vacuo to yield the starting material lithium carboxylate as an off-white solid and used for these amide bonds. The lithium carboxylate suspension prepared in advance and suspended in N , N -dimethylformamide (0.50 mL) was stirred, followed by HATU (31.7 mg, 0.083 mmol) and N- (2-methoxyethyl) methylamine (0.022 mL, 0.21). mmol) was added. The reaction mixture was stirred at rt for 1 h. The reaction mixture was quenched with saturated aqueous NH ₄ Cl (20 mL) and extracted with EtOAc (30 mL). The organic layer was separated, washed with brine (15 mL), dried over MgSO ₄ , filtered and concentrated in vacuo. The residue was purified by chromatography (silica gel; 0% to 100% EtOAc in heptanes containing 0.3% AcOH), followed by chromatography (silica gel; 0% to 100% EtOAc in heptanes) to give 2 -((1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-methoxy-11 ', 12'-dimethyl-13', 13 '-Dioxido-15'-oxo-3,4-dihydro-2H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0- 3,6 ~ 0.0 ~ 19,24 ~] penta Kosa [8,16,18,24] tetraene; -7'- yl) - N - (2- methoxyethyl) - N - methyl acetamide white Obtained as a solid (23 mg, 0.031 mmol, 74% yield). ¹ H NMR (400 MHz, Chloroform- d ) δ ppm 8.27 (0.4 H, s) 8.10 (0.6 H, s) 7.69 (1 H, d, J = 8.61 Hz) 7.17 (1 H, dd, J = 8.41, 2.15 Hz) 7.08 (1 H, d, J = 1.96 Hz) 6.90-7.06 (3 H, m) 5.84-5.90 (1 H, m) 5.72-5.83 (1 H, m) 4.28 (0.6 H, q, J = 7.04 Hz) 4.19 (0.4 H, q, J = 7.04 Hz) 4.05 (1.2 H, s) 4.04 (0.8 H, s) 3.95 (0.4 H, d, J = 10.17 Hz) 3.91 (0.6 H, d, J = 10.17 Hz) 3.52-3.77 (4 H, m) 3.22-3.34 (7 H, m) 2.97-3.19 (6 H, m) 2.57-2.82 (4 H, m) 2.38-2.54 (1 H, m) 1.99 -2.23 (4 H, m) 1.72-1.99 (5 H, m) 1.57-1.68 (1 H, m) 1.46-1.51 (3 H, m) 1.27-1.37 (1 H, m) 1.04-1.11 (3 H , m). MS (ESI, + ve) m / z 742.2 [M + H] ⁺ .

Example 100006

(1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -7 '-(2- (1-azetidinyl) -2-oxoethyl) -6-chloro-7' -Methoxy-11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-[20] oxa [13] thia [1,14] diaza Tetracyclo [14.7.2.0 ~ 3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraene] -15'-one 13 ', 13'-dioxide

((1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-methoxy-11 ', 12'-dimethyl-13', 13'- Dioxido-15'-oxo-3,4-dihydro-2H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diaza tetracyclo [14.7.2.0-3] , 6 ~ .0 ~ 19,24 ~] Pentacosa [8,16,18,24] tetraen] -7'-yl) acetic acid (28 mg, 0.042 mmol) was dissolved in THF (0.5 mL) and lithium hydroxide (2.0 M in water, 0.083 mL, 0.17 mmol) was added. The mixture was stirred at room temperature for 10 minutes and then concentrated in vacuo to yield the starting material lithium carboxylate as an off-white solid and used for these amide bonds. The lithium carboxylate suspension prepared in advance and suspended in N , N -dimethylformamide (0.25 mL) was stirred and HATU (31.7 mg, 0.083 mmol) and azetidine (0.014 mL, 0.209 mmol) were added. The reaction mixture was stirred at rt for 1 h. The reaction mixture was quenched with saturated aqueous NH ₄ Cl (10 mL) and extracted with EtOAc (15 mL). The organic layer was separated, washed with brine (10 mL), dried over MgSO ₄ , filtered and concentrated in vacuo. The residue is purified by chromatography (silica gel; 0% to 100% EtOAc in heptanes containing 0.3% AcOH), followed by chromatography (silica gel; 0% to 100% EtOAc in heptanes) ( 1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -7 '-(2- (1-azetidinyl) -2-oxoethyl) -6-chloro-7'- Methoxy-11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-[20] oxa [13] thia [1,14] diazate Cyclo [14.7.2.0-3,6-0.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ', 13'-dioxide was obtained as a white solid. (22 mg, 0.031 mmol, 74% yield). ¹ H NMR (400 MHz, Chloroform- d ) δ ppm 8.21 (1 H, br s) 7.68 (1 H, d, J = 8.61 Hz) 7.13-7.20 (1 H, m) 7.06-7.09 (1 H, m ) 6.88-6.97 (3 H, m) 5.70-5.86 (2 H, m) 4.23-4.39 (3 H, m) 3.98-4.11 (5 H, m) 3.70 (1 H, d, J = 14.28 Hz) 3.22 -3.32 (2 H, m) 3.08-3.18 (4 H, m) 2.81-2.88 (1 H, m) 2.67-2.79 (2 H, m) 2.33-2.46 (2 H, m) 2.19-2.31 (2 H , m) 1.72-2.19 (9 H, m) 1.56-1.69 (1 H, m) 1.49 (3 H, d, J = 6.85 Hz) 1.25-1.36 (1 H, m) 1.06 (3 H, d, J = 6.65 Hz). MS (ESI, + ve) m / z 710.2 [M + H] ⁺ .

Example 100007 and Example 100016

(1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7 ', 11', 12'-trimethyl-7 '-(2- (4-morphopoly Yl) ethoxy) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0 ~ 3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraene] -15'-on 13 ', 13'-dioxide (Example 100007) and (1S, 3'R , 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-7 ', 11', 12'-trimethyl-3,4-dihydro-2H, 15 ' H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6-0.0-19,24-] pentacosa [8, Tetraene] -15'-on 13 ', 13'-dioxide (Example 100016)

Step 1: (1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-7 ', 11', 12'-trimethyl-3, 4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19 , 24 ~] pentacosa [8,16,18,24] tetraene] -15'-on 13 ', 13'-dioxide

(1S, 3'R, 6'R, 8'E, 11'S, 12'R) -6-chloro-11 ', 12'-dimethyl-3,4-dihydro- in tetrahydrofuran (3 mL) 2H, 7'H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazettracyclo [14.7.2.0-3,6-0.0-19, 24 to] pentacosa [8,16,18,24] tetraene] -7 ', 15'-dione 13', 13'-dioxide (184 mg, 0.308 mmol) in a stirred solution of lanthanum chloride (III)- Bis (lithium chloride) complex (0.5 M solution in THF, 0.616 mL, 0.308 mmol) was added at 0 ° C. After the mixture was stirred at 0 ° C. for 45 minutes, methylmagnesium bromide (3.0 M solution in diethyl ether, 0.462 mL, 1.39 mmol) was added dropwise via syringe. The reaction mixture was warmed to room temperature and stirred for 18 hours. The reaction mixture was quenched with saturated NH ₄ Cl (30 mL) and extracted with EtOAc (45 mL). The organic layer was separated, washed with brine (30 mL), dried over MgSO ₄ , filtered and concentrated in vacuo. The residue was purified by chromatography (silica gel; 0% to 75% EtOAc in heptanes containing 0.3% AcOH) (1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-Chloro-7'-hydroxy-7 ', 11', 12'-trimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13 ] Thia [1,14] diaza tetracyclo [14.7.2.0-3,6-0.0-19,24-] pentacosa [8,16,18,24] tetraene] -15'-one 13 ', 13'-dioxide (which is the second eluting diastereomer in the column) was obtained as a white solid (92 mg, 0.150 mmol, 49% yield) ¹ H NMR (400 MHz, Dichloromethane-d2) δ 7.71 ( d, J = 8.6 Hz, 1H), 7.18 (dd, J = 2.2, 8.5 Hz, 1H), 7.10 (d, J = 2.2 Hz, 1H), 7.00-6.89 (m, 3H), 5.90-5.76 (m , 2H), 4.35-4.24 (m, 1H), 4.11-4.04 (m, 2H), 3.84 (br d, J = 14.9 Hz, 1H), 3.73 (d, J = 14.3 Hz, 1H), 3.28 (d , J = 14.3 Hz, 1H), 3.05 (dd, J = 10.4, 15.3 Hz, 1H), 2.86-2.70 (m, 2H), 2.46-2.33 (m, 1H), 2.27 (q, J = 9.3 Hz, 1H), 2.18-2.10 (m, 1H), 2.07 (br d, J = 2.5 Hz, 1H), 2.05-2.01 (m, 2H), 2.02-1.91 (m, 3H), 1.89-1.78 (m, 3H), 1.69-1.60 (m, 1H), 1.52 (s, 3H), 1.47 (d, J = 7.2 Hz, 3H), 1.44-1.36 (m, 1H), 1.04 (d, J = 6.8 Hz, 3H) MS (ESI, + ve) m / z 613.3 [M + H] ⁺ .

Step 2: (1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7 ', 11', 12'-trimethyl-7 '-(2- (4 -Morpholinyl) ethoxy) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatracyclo [14.7 .2.0 ~ 3,6 ~ .0 ~ 19,24 ~] Pentacosa [8,16,18,24] tetraene] -15'-on 13 ', 13'-dioxide

(1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-7 ', 11', 12'-trimethyl-3,4-di Hydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~ ] Pentacosa [8,16,18,24] tetraene] -15'-one 13 ', 13'-dioxide (33 mg, 0.054 mmol), 4- (2-bromoethyl) morpholine hydrobromide (296 mg, 1.08 mmol), and sodium hydride (60% dispersion in mineral oil, 86 mg, 2.2 mmol) were mixed in N , N -dimethylformamide (1.5 mL). The reaction mixture was stirred at rt for 20 h. The reaction mixture was quenched with saturated aqueous NH ₄ Cl (20 mL) and extracted twice with EtOAc (30 mL). The combined organic layers were washed with brine (15 mL), dried over MgSO ₄ , filtered and concentrated in vacuo. The residue is eluted with chromatography (silica gel; 50% to 100% gradient EtOAc in DCM until the starting material is eluted, followed by 0% to 10% gradient (2M NH _{3 in} MeOH) in DCM. Eluting), (1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7 ', 11', 12'-trimethyl-7 '-(2 -(4-morpholinyl) ethoxy) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazate Cyclo [14.7.2.0-3,6-0.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ', 13'-dioxide was obtained as an off-white solid. (25 mg, 0.034 mmol, 64% yield). ¹ H NMR (400 MHz, Chloroform- d ) δ 7.68 (1 H, d, J = 8.41 Hz) 7.17 (1 H, dd, J = 8.41, 2.15 Hz) 7.08 (1 H, d, J = 2.15 Hz) 6.89-6.96 (3 H, m) 5.82 (1 H, ddd, J = 15.85, 9.59, 2.74 Hz) 5.65 (1 H, d, J = 15.85 Hz) 4.29 (1 H, q, J = 7.11 Hz) 4.00 4.11 (2 H, m) 3.83 (1 H, d, J = 14.67 Hz) 3.68-3.77 (5 H, m) 3.33-3.46 (2 H, m) 3.26 (1 H, d, J = 14.28 Hz) 3.00 (1 H, dd, J = 15.16, 10.66 Hz) 2.69-2.84 (2 H, m) 2.52-2.61 (6 H, m) 2.40 (1 H, quin, J = 8.95 Hz) 2.28 (1 H, q , J = 9.13 Hz) 1.74-2.21 (9 H, m) 1.52-1.64 (1 H, m) 1.48 (3 H, d, J = 7.04 Hz) 1.33-1.43 (4 H, m) 1.04 (3 H, d, J = 6.85 Hz). MS (ESI, + ve) m / z 726.3 [M + H] ⁺ .

Example 100008

2-((1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-methoxy-11 ', 12'-dimethyl-13', 13 '-Dioxido-15'-oxo-3,4-dihydro-2H-spiro [naphthalene-1,22'-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0 ~ 3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraen] -7'-yl) -N-methyl-N- (2-methyl-2-propanyl) Acetamide

((1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'- in oxalyl chloride (10 μL, 0.11 mmol) and dichloromethane (1 mL) Methoxy-11 ', 12'-dimethyl-13', 13'-dioxido-15'-oxo-3,4-dihydro-2H-spiro [naphthalene-1,22 '-[20] oxa [ 13] thia [1,14] diazatetracyclo [14.7.2.0-3,6-0.0-19,24-] pentacosa [8,16,18,24] tetraen] -7'-yl) acetic acid To the stirred solution of (37 mg, 0.055 mmol) was added dropwise DMF. The reaction mixture was stirred at rt for 20 min and then concentrated in vacuo. The resulting yellow residue was dissolved in dichloromethane (1 mL) and N -tert-butylmethylamine (0.066 mL, 0.55 mmol) was added. The reaction mixture was stirred for 40 minutes at room temperature. The reaction mixture was quenched with saturated aqueous NH ₄ Cl (20 mL) and extracted with EtOAc (30 mL). The organic layer was separated, washed with brine (20 mL), dried over MgSO ₄ , filtered and concentrated in vacuo. The residue was purified by chromatography (silica gel; 0% to 50% EtOAc in 0.3 heptanes containing 0.3% AcOH) in 2-((1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-Chloro-7'-methoxy-11 ', 12'-dimethyl-13', 13'-dioxido-15'-oxo-3,4-dihydro-2H-spiro [ Naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18, 24] tetraen] -7'-yl) -N-methyl-N- (2-methyl-2-propanyl) acetamide was obtained as an off-white solid (18 mg, 0.024 mmol, 44% yield). ¹ H NMR (400 MHz, Chloroform- d ) δ 8.01 (1 H, s) 7.68 (1 H, d, J = 8.41 Hz) 7.17 (1 H, dd, J = 8.51, 2.25 Hz) 7.08 (1 H, d, J = 1.96 Hz) 6.88-6.96 (3 H, m) 5.68-5.81 (2 H, m) 4.33 (1 H, q, J = 7.43 Hz) 4.07 (2 H, s) 3.85 (1 H, d , J = 15.06 Hz) 3.71 (1 H, d, J = 14.28 Hz) 3.22-3.36 (2 H, m) 3.11 (3 H, s) 3.01-3.09 (5 H, m) 2.68-2.84 (2 H, m) 2.59 (1 H, d, J = 15.85 Hz) 2.33-2.44 (1 H, m) 2.06-2.23 (2 H, m) 1.74-2.06 (7 H, m) 1.55-1.66 (1 H, m) 1.24-1.52 (13 H, m) 1.06 (3 H, d, J = 6.65 Hz). MS (ESI, + ve) m / z 762.3 [M + Na] ⁺ .

Example 100009

2-((1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-methoxy-11 ', 12'-dimethyl-13', 13 '-Dioxido-15'-oxo-3,4-dihydro-2H-spiro [naphthalene-1,22'-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0 ~ 3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraen] -7'-yl) -N-methylacetamide

((1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-methoxy-11 ', 12'-dimethyl-13', 13'- Dioxido-15'-oxo-3,4-dihydro-2H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diaza tetracyclo [14.7.2.0-3] , 6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraen] -7'-yl) acetic acid (50 mg, 0.074 mmol) was dissolved in THF (2 mL) and lithium hydroxide (2.0 M in water, 0.149 mL, 0.358 mmol) was added. The mixture was stirred at room temperature for 10 minutes and then concentrated in vacuo to yield the starting material lithium carboxylate as an off-white solid and used for these amide bonds. Stir the lithium carboxylate suspension prepared in advance and suspended in N, N -dimethylformamide (2 mL) and add HATU (42.0 mg, 0.112 mmol) and methylamine (2.0 M in THF, 0.112 mL, 0.223 mmol) It was. The reaction mixture was stirred at rt for 30 min. The reaction mixture was diluted with water and EtOAc and transferred to a separatory funnel. 1.0 M HCl was added and the phases were mixed. The organic layer was separated, washed sequentially with 1.0 M LiCl and brine, dried over magnesium sulfate and concentrated under reduced pressure. Purification via silica gel flash chromatography (using EtOAc in heptane (containing 0.3% AcOH) in a gradient of 50% to 100%) 2-((1S, 3'R, 6'R, 7'S, 8'E, 11'S) , 12'R) -6-Chloro-7'-methoxy-11 ', 12'-dimethyl-13', 13'-dioxido-15'-oxo-3,4-dihydro-2H-spiro [Naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ 0.19 ~ 24,24] pentacosa [8,16,18 , 24] tetraen] -7'-yl) -N-methylacetamide was obtained as a white solid (44 mg, 0.064 mmol, 86% yield). ¹ H NMR (300 MHz, Dichloromethane-d2) δ 7.69-7.79 (m, 1 H) 7.19 (br dd, J = 8.84, 1.10 Hz, 1 H) 7.12 (s, 1 H) 6.88-7.03 (m , 3 H) 6.74-6.86 (m, 1 H) 5.75-5.89 (m, 1 H) 5.62-5.73 (m, 1 H) 4.21-4.36 (m, 1 H) 4.09 (s, 2 H) 3.91-4.04 (m, 1 H) 3.72 (br d, J = 15.05 Hz, 1 H) 3.29 (br d, J = 14.03 Hz, 1 H) 3.16 (s, 3 H) 2.92-3.09 (m, 2 H) 2.73- 2.90 (m, 6 H) 2.51-2.66 (m, 2 H) 2.37-2.49 (m, 1 H) 1.67-2.25 (m, 11 H) 1.48 (br d, J = 7.02 Hz, 3 H) 1.22-1.43 (m, 6H) 1.06 (br d, J = 6.58 Hz, 3H). MS (ESI, + ve) m / z 652.0 [M−OMe] ⁺ .

Example 100010

(1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-methoxy-11 ', 12'-dimethyl-7'-(2-oxo -2- (1-pyrrolidinyl) ethyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diaza Tetracyclo [14.7.2.0 ~ 3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraene] -15'-one 13 ', 13'-dioxide

Step 1: methyl ((1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-11 ', 12'-dimethyl-13' , 13'-dioxido-15'-oxo-3,4-dihydro-2H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazettracyclo [14.7 .2.0 ~ 3,6 ~ .0 ~ 19,24 ~] Pentacosa [8,16,18,24] tetraene] -7'-yl) acetate

A flame dried round bottom flask was charged with tetrahydrofuran (6.28 mL) and lithium diisopropylamide (2.0 M solution in heptane / tetrahydrofuran / ethylbenzene, 7.54 mL, 15.1 mmol). The solution was cooled to −78 ° C. and then a solution of methyl acetate (1.197 mL, 15.07 mmol) in tetrahydrofuran (6.28 mL) was added dropwise and the reaction stirred at −78 ° C. for 45 minutes. The flask was equipped with an addition funnel and then (1S, 3'R, 6'R, 8'E, 11'S, 12'R) -6-chloro-11 ', 12'-die in tetrahydrofuran (12.56 mL). Methyl-3,4-dihydro-2H, 7'H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0- 3,6 ~ .0 ~ 19,24 ~] Pentacosa [8,16,18,24] tetraene] -7 ', 15'-dione 13', 13'-dioxide (1.5 g, 2.5 mmol) solution Filled with The reaction was stirred at -78 ° C for 30 minutes. The reaction was quenched with water and warmed to room temperature. The reaction was diluted with water and EtOAc and transferred to a separatory funnel. 1 M HCl was added. The organic phases were separated by mixing the phases, washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. Purification of the crude residue via silica gel flash chromatography (using EtOAc in heptane with 0.3% AcOH) in a gradient of 20% to 70%, yielded methyl ((1S, 3'R, 6'R, 7'S, 8 '). E, 11'S, 12'R) -6-Chloro-7'-hydroxy-11 ', 12'-dimethyl-13', 13'-dioxido-15'-oxo-3,4-dihydro- 2H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6-0.0-19,24-] pentacosa [8, 16,18,24] tetraen] -7'-yl) acetate (which is the second eluting diastereomer) was obtained as a white solid (0.666 g, 0.992 mmol, 40% yield). ¹ H NMR (300 MHz, Dichloromethane-d2) δ 8.06-8.25 (m, 1 H) 7.74 (d, J = 8.62 Hz, 1 H) 7.20 (br d, J = 8.77 Hz, 1 H) 7.13 ( s, 1 H) 6.96 (s, 2 H) 6.92 (s, 1 H) 5.64-5.81 (m, 2 H) 4.06-4.25 (m, 3 H) 3.80 (s, 3 H) 3.75 (br d, J = 14.03 Hz, 1 H) 3.70 (s, 1 H) 3.31 (d, J = 14.18 Hz, 1 H) 3.00-3.11 (m, 1 H) 2.91-3.00 (m, 1 H) 2.69-2.87 (m, 3 H) 2.32-2.56 (m, 2 H) 1.79-2.21 (m, 9 H) 1.59-1.71 (m, 2 H) 1.46 (d, J = 7.16 Hz, 4 H) 1.34-1.39 (m, 4 H ) 1.06 (d, J = 6.58 Hz, 3 H). MS (ESI, + ve) m / z 671.2 [M + H] ⁺ .

Step 2: (1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-11 ', 12'-dimethyl-7'-( 2-oxo-2- (1-pyrrolidinyl) ethyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14 ] Diazatetracyclo [14.7.2.0 ~ 3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraene] -15'-one 13 ', 13'-dioxide

Methyl ((1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-11 ', 12'-dimethyl in THF (10.22 mL) -13 ', 13'-dioxido-15'-oxo-3,4-dihydro-2H-spiro [naphthalene-1,22'-[20] oxa [13] thia [1,14] diazate Lithium hydroxide in solution of cyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraen] -7'-yl) acetate (0.343 g, 0.511 mmol) (2.0 M in water, 0.639 mL, 1.28 mmol) was added. The reaction was stirred at rt overnight. The reaction was concentrated under reduced pressure and used without further purification. HATU (0.069 g, 0.18 mmol) was added to a suspension of lithium hydroxide previously produced and suspended in DMF (2.5 mL) followed by pyrrolidin (0.050 mL, 0.60 mmol). The reaction was stirred at rt for 30 min. The reaction was diluted with water and EtOAc and transferred to a separatory funnel. 1.0 M HCl was added and the phases were mixed. The organic layer was separated, washed sequentially with 1.0 M LiCl and brine, dried over magnesium sulfate and concentrated under reduced pressure. Purification via silica gel flash chromatography (using EtOAc in heptane (containing 0.3% AcOH) in a gradient of 75% to 100%) (1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12 '). R) -6-chloro-7'-hydroxy-11 ', 12'-dimethyl-7'-(2-oxo-2- (1-pyrrolidinyl) ethyl) -3,4-dihydro-2H , 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6-0.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ', 13'-dioxide was obtained as a white solid (0.0608 g, 0.086 mmol, 71% yield). MS (ESI, + ve) m / z 710.3 [M + H] ⁺ .

Step 3: (1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-methoxy-11 ', 12'-dimethyl-7'-( 2-oxo-2- (1-pyrrolidinyl) ethyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14 ] Diazatetracyclo [14.7.2.0 ~ 3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraene] -15'-one 13 ', 13'-dioxide

(1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-11 ', 12'-dimethyl-7 in THF (0.856 mL) '-(2-oxo-2- (1-pyrrolidinyl) ethyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-[20] oxa [13] thia [ 1,14] diatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraene] -15'-one 13 ', 13'- The dioxide (0.0608 g, 0.086 mmol) solution was cooled to 0 ° C. and then sodium hydride (0.017 g, 0.428 mmol) was added. The reaction was stirred for 15 minutes, then iodine methane (0.053 mL, 0.856 mmol) was added, the reaction was allowed to warm to room temperature and stirred for 1 hour. More iodine methane (0.150 mL) was added and the reaction stirred overnight at room temperature. Further MeI (0.15 mL) was added in one portion and the reaction was continued for 6 hours at room temperature. The reaction was quenched with water and diluted with water and EtOAc. The reaction was transferred to a separatory funnel and 1 M HCl was added. The organic phases were separated by mixing the phases, washed with brine and dried over magnesium sulfate. The crude was purified via silica gel flash chromatography (using 100% EtOAc with 0.6% AcOH). Repeat the reaction once more on the same scale, combine the materials from both reactions and further purify it by preparative supercritical fluid chromatography (SFC) using the following conditions (1S, 3'R, 6 '). R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-methoxy-11 ', 12'-dimethyl-7'-(2-oxo-2- (1-pyrrolidinyl ) Ethyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3, 6 ~ .0 ~ 19,24 ~] Pentacosa [8,16,18,24] tetraen] -15'-one 13 ', 13'-dioxide was obtained as a white solid (0.018 g, 0.025 mmol, 15 % Yield): Diol column (21.2 × 250 mm, 5 μm); 20% MeOH in C0 _{2 with} 20 mM NH ₃ . ¹ H NMR (300 MHz, Dichloromethane-d2) δ 7.75 (br d, J = 8.18 Hz, 1 H) 7.20 (br d, J = 8.48 Hz, 1 H) 7.12 (br s, 2 H) 7.00- 7.06 (m, 1 H) 6.90-6.98 (m, 1 H) 5.75-5.99 (m, 2 H) 4.13-4.24 (m, 1 H) 4.10 (s, 2 H) 3.86-3.96 (m, 1 H) 3.74 (br d, J = 14.32 Hz, 1 H) 3.57-3.68 (m, 2 H) 3.41-3.54 (m, 2 H) 3.34 (br d, J = 14.62 Hz, 1 H) 3.07-3.25 (m, 4 H) 3.03 (br d, J = 15.93 Hz, 1 H) 2.69-2.92 (m, 2 H) 2.46-2.67 (m, 2 H) 2.04-2.26 (m, 4 H) 1.74-2.03 (m, 9 H) 1.49-1.73 (m, 9H) 1.46 (br d, J = 6.72 Hz, 3H) 1.29-1.41 (m, 2H) 1.03-1.14 (m, 3H). MS (ESI, + ve) m / z 692.2 [M−OMe] ⁺ .

Example 100011

(1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7 '-(4-((9aS) -hexahydropyrazino [2,1-c] [1,4] oxazine-8 (1H) -yl) -1-butyn-1-yl) -7'-methoxy-11 ', 12'-dimethyl-3,4-dihydro-2H, 15 'H-spiro [naphthalene-1,22'-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6-0.0-19,24-] pentacosa [8 , 16,18,24] tetraene] -15'-on 13 ', 13'-dioxide

Step 1: (1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7 '-(4-((dimethyl (2-methyl-2-propanyl ) Silyl) oxy) -1-butyn-1-yl) -7'-hydroxy-11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraene -15'-on 13 ', 13'-dioxide

2.5 M in toluene (4.0 mL, 10 mmol) in a cold solution (-78 ° C.) of 4- (tert-butyldimethylsilyl) -1-butyene (2.50 mL, 12.1 mmol) in tetrahydrofuran (30 mL) Butyl lithium was added dropwise through a syringe over 15 minutes. After 1 h, (1S, 3'R, 6'R, 8'E, 11'S, 12'R) -6-chloro-11 ', 12'-dimethyl-3,4-di in THF (10 mL) Hydro-2H, 7'H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraene] -7 ', 15'-dione 13', 13'-dioxide (1.008 g, 1.688 mmol) was added dropwise for 1 hour Stirred. The reaction was quenched with pH 7 buffer (10 mL) and warmed to room temperature. The aqueous layer was extracted three times with EtOAc. The combined organic layers were washed with brine and dried over Na ₂ S0 ₄ . The solution was filtered, evaporated onto silica gel and purified by flash chromatography eluting with 0.3% AcOH in EtOAc to 0.3% AcOH in heptane (0: 1 to 1: 3) (1S, 3'R, 6). 'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-(4-((dimethyl (2-methyl-2-propanyl) silyl) oxy) -1-butyn-1 -Yl) -7'-hydroxy-11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-[20] oxa [13] thia [ 1,14] diatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraene] -15'-one 13 ', 13'- Dioxide was obtained as a white solid (468 mg, 36%). MS (ESI, cation) m / z 763.4 (M + l) ⁺ .

Step 2: (1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7 '-(4-((dimethyl (2-methyl-2-propanyl ) Silyl) oxy) -1-butyn-1-yl) -7'-methoxy-11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraene -15'-on 13 ', 13'-dioxide

(1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7 '-(4-((dimethyl (2-methyl) in tetrahydrofuran (10 mL) -2-propanyl) silyl) oxy) -1-butyn-1-yl) -7'-hydroxy-11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [ Naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18, To a cooled solution of tetraene] -15'-on 13 ', 13'-dioxide (0.510 g, 0.653 mmol) (0 ° C.), 60% sodium hydride (0.211 g, 5.28 mmol) in mineral oil was added several times. . After 15 minutes iodomethane (0.160 mL, 2.58 mmol) was added and the reaction was allowed to warm to room temperature overnight. The reaction mixture was quenched with pH 7 buffer and partitioned between EtOAc and water. The aqueous layer was extracted three times with EtOAc, then the combined organic layers were washed with brine, evaporated onto silica gel and flash chromatography eluting with 0.3% AcOH in EtOAc: 0.3% AcOH in heptane (0: 1 to 1: 3). Purified by (Isco, 25 g), (1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7 '-(4-((dimethyl (2 -Methyl-2-propaneyl) silyl) oxy) -1-butyn-1-yl) -7'-methoxy-11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H- Spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6-0.0-19,24-] pentacosa [8,16, 18,24] tetraen] -15'-one 13 ', 13'-dioxide was obtained as a white solid (368 mg, 71% yield). MS (ESI, cation) m / z 795.4 (M + l) ⁺ .

Step 3: (1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7 '-(4-hydroxy-1-butyn-1-yl) -7 '-Methoxy-11', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] dia Zatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] Pentacosa [8,16,18,24] tetraene] -15'-one 13 ', 13'-dioxide

(1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7 '-(4-((dimethyl (2-methyl) in tetrahydrofuran (5 mL) -2-propanyl) silyl) oxy) -1-butyn-1-yl) -7'-methoxy-11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [ Naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18, To a room temperature solution of tetraene] -15'-one 13 ', 13'-dioxide (0.365 g, 0.459 mmol), 1 M tetrabutylammonium fluoride in tetrahydrofuran (1.5 mL, 1.5 mmol) was added via syringe. It was. The solution was evaporated onto silica gel and purified by flash chromatography eluting with 0.3% AcOH in EtOAc to 0.3% AcOH (0: 1 to 1: 1) in heptane (1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7 '-(4-hydroxy-1-butyn-1-yl) -7'-methoxy-11', 12'-dimethyl- 3,4-Dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6-0.0 19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ', 13'-dioxide was obtained as a white solid (279 mg, 89% yield). MS (ESI, cation) m / z 681.3 (M + l) ⁺ .

Step 4: (1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-Chloro-7 '-(4-((9aS) -hexahydropyrazino [2,1 -c] [1,4] oxazin-8 (1H) -yl) -1-butyn-1-yl) -7'-methoxy-11 ', 12'-dimethyl-3,4-dihydro- 2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] penta Cosa [8,16,18,24] tetraene] -15'-on 13 ', 13'-dioxide

(1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7 '-(4-hydroxy-1-butyn-1 in dichloromethane (1 mL) -Yl) -7'-methoxy-11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-[20] oxa [13] thia [ 1,14] diatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraene] -15'-one 13 ', 13'- Triethylamine (0.020 mL, 0.14 mmol) was added to a cooled solution of dioxide (0.023 g, 0.034 mmol) (0 ° C.), followed by methanesulfonyl chloride (0.015 mL, 0.19 mmol) and the reaction was 20 minutes. Was stirred. To the reaction was added a slurry of (S) -octahydropyrazino [2,1-c] morpholine dihydrochloride (0.067 g, 0.31 mmol) and triethylamine in dichloromethane (1 mL) and the reaction at room temperature. Stir for 85 hours and at 45 ° C. for 4 hours. The reaction was cooled to room temperature, diluted with DCM, evaporated onto silica gel and purified by flash chromatography (Isco, 4 g) eluting with 25% EtOH / EtOAc: heptane (0: 1 to 1: 0). To a pale yellow solid (12.6 mg, 46% yield). ¹ H NMR (400 MHz, CD ₂ Cl ₂ ) δ 7.72 (d, J = 8.41 Hz, 1 H), 7.20 (s, 1 H), 7.17 (dd, J = 8.51, 2.05 Hz, 1 H), 7.09 (d, J = 2.15 Hz, 1 H), 6.85-6.98 (m, 2 H), 6.20-6.39 (m, 1 H), 5.52 (d, J = 15.84 Hz, 1 H), 4.32 (d, J = 15.65 Hz, 1 H), 4.26 (d, J = 6.46 Hz, 1 H), 4.14 (d, J = 12.13 Hz, 1 H), 4.00-4.11 (m, 2H), 3.75 (dd, J = 11.15, 2.93 Hz, 1 H), 3.69 (d, J = 14.08 Hz, 1 H), 3.51-3.64 (m, 2 H), 3.27 (d, J = 14.28 Hz, 1 H), 3.07-3.19 (m , 4H), 3.01 (dd, J = 15.26, 10.37 Hz, 1H), 2.87 (d, J = 7.43 Hz, 1H), 2.74-2.83 (m, 3H), 2.50-2.72 (m, 8 H), 2.37-2.49 (m, 1 H), 2.08-2.27 (m, 7 H), 1.77-1.99 (m, 5 H), 1.57-1.75 (m, 2 H), 1.34-1.51 (m, 4 H), 1.03 (d, J = 6.85 Hz, 3 H). MS (ESI, cation) m / z 805.3 (M + l) ⁺ .

Example 100012

(1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-methoxy-11 ', 12'-dimethyl-7'-(4- ( 4-morpholinyl) -1-butyn-1-yl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14 ] Diazatetracyclo [14.7.2.0-3,6-0.0-19,24-] pentacosa [8,16,18,24] tetraene] -15'-one 13 ', 13'-dioxide or ( 1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-methoxy-11 ', 12'-dimethyl-7'-(4- (4-morpholinyl) -1-butyn-1-yl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1, 14] diaza tetracyclo [14.7.2.0 to 3,6 to .0 to 19,24 to] pentacosa [8,16,18,24] tetraene] -15'-on 13 ', 13'-dioxide

Step 1: (1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7 '-(4-((dimethyl (2-methyl-2-propanyl ) Silyl) oxy) -1-butyn-1-yl) -7'-hydroxy-11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraene -15'-one 13 ', 13'-dioxide and (1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-(4- ( (Dimethyl (2-methyl-2-propanyl) silyl) oxy) -1-butyn-1-yl) -7'-hydroxy-11 ', 12'-dimethyl-3,4-dihydro-2H , 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6-0.0-19,24-] pentacosa [8,16,18,24] tetraene] -15'-on 13 ', 13'-dioxide

To a cold solution (-78 ° C.) of 4- (tert-butyldimethylsilyloxy) -1-butyene (0.600 mL, 2.91 mmol) in tetrahydrofuran (9 mL) 2.5 in toluene (1.00 mL, 2.50 mmol) M butyllithium solution was added dropwise over 10 minutes. After 1 h, (1S, 3'R, 6'R, 8'E, 11'S, 12'R) -6-chloro-11 ', 12'-dimethyl-3,4-di in THF (2 mL) Hydro-2H, 7'H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ A solution of 19,24-] pentacosa [8,16,18,24] tetraene] -7 ', 15'-dione 13', 13'-dioxide (0.249 g, 0.417 mmol) was added dropwise via syringe. . After 1 h, the reaction mixture was quenched with pH 7 buffer, partitioned between EtOAc and brine and the aqueous layer was extracted three times with EtOAc. The combined organic layers were evaporated onto silica gel and purified by flash chromatography (Isco, 12 g) eluting with 0.3% AcOH in EtOAc: 0.3% AcOH in heptane (0: 1 to 1: 3) (1S, 3 'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-(4-((dimethyl (2-methyl-2-propanyl) silyl) oxy) -1 -Butyn-1-yl) -7'-hydroxy-11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-[20] oxa [ 13] thia [1,14] diatetracyclo [14.7.2.0-3,6-0.0-19,24-] pentacosa [8,16,18,24] tetraene] -15'-one 13 ' , 13'-dioxide and (1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7 '-(4-((dimethyl (2-methyl -2-propanyl) silyl) oxy) -1-butyn-1-yl) -7'-hydroxy-11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [ Naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18, 24] tetraen] -15'-on 13 ', 13'-dioxide was obtained as a white solid (254 mg, 78% yield). MS (ESI, cation) m / z 784.5 (M + l) ⁺ .

Step 2: (1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7 '-(4-((dimethyl (2-methyl-2-propanyl ) Silyl) oxy) -1-butyn-1-yl) -7'-methoxy-11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraene -15'-one 13 ', 13'-dioxide and (1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-(4- ( (Dimethyl (2-methyl-2-propanyl) silyl) oxy) -1-butyn-1-yl) -7'-methoxy-11 ', 12'-dimethyl-3,4-dihydro-2H , 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6-0.0-19,24-] pentacosa [8,16,18,24] tetraene] -15'-on 13 ', 13'-dioxide

(1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7 '-(4-((dimethyl (2-methyl) in tetrahydrofuran (5 mL) -2-propanyl) silyl) oxy) -1-butyn-1-yl) -7'-hydroxy-11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [ Naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18, 24] tetraene] -15'-one 13 ', 13'-dioxide and (1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7' -(4-((dimethyl (2-methyl-2-propanyl) silyl) oxy) -1-butyn-1-yl) -7'-hydroxy-11 ', 12'-dimethyl-3,4 -Dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazettracyclo [14.7.2.0-3,6-0.0-19, 24 ~] Pentacosa [8,16,18,24] tetraen] -15'-one 13 ', 13'-dioxide (0.254 g, 0.325 mmol) in a cold solution (0 ° C.) in 60% NaH (mineral oil) 0.105 g, 2.63 mmol) was added once. After 10 minutes, iomethane (0.080 mL, 1.3 mmol) was added via syringe and the reaction was allowed to warm to room temperature overnight. The reaction mixture was quenched with pH 7 buffer and partitioned between EtOAc and water. The combined organic layers were evaporated onto silica gel and purified by flash chromatography (Isco, 25 g) eluting with 0.3% AcOH in EtOAc: 0.3% AcOH in heptane (0: 1 to 1: 3) (1S, 3 '). R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7 '-(4-((dimethyl (2-methyl-2-propanyl) silyl) oxy) -1- Butyn-1-yl) -7'-methoxy-11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-[20] oxa [13 ] Thia [1,14] diaza tetracyclo [14.7.2.0-3,6-0.0-19,24-] pentacosa [8,16,18,24] tetraene] -15'-one 13 ', 13'-dioxide and (1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7 '-(4-((dimethyl (2-methyl- 2-propanyl) silyl) oxy) -1-butyn-1-yl) -7'-methoxy-11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene -1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6-0.0-19,24-] pentacosa [8,16,18,24 ] Tetraen] -15'-one 13 ', 13'-dioxide was obtained as a white solid (173 mg, 67% yield) ). MS (ESI, cation) m / z 796.3 (M + l) ⁺ .

Step 3: (1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7 '-(4-hydroxy-1-butyn-1-yl) -7 '-Methoxy-11', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] dia Jatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ', 13'-dioxide and (1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7 '-(4-hydroxy-1-butyn-1-yl) -7'-methoxy -11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-[20] oxa [13] thia [1,14] diazettracyclo [ 14.7.2.0 ~ 3,6 ~ .0 ~ 19,24 ~] Pentacosa [8,16,18,24] tetraene] -15'-on 13 ', 13'-dioxide

(1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7 '-(4-((dimethyl (2-methyl) in tetrahydrofuran (3 mL) -2-propanyl) silyl) oxy) -1-butyn-1-yl) -7'-methoxy-11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [ Naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18, 24] tetraene] -15'-one 13 ', 13'-dioxide and (1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7' -(4-((dimethyl (2-methyl-2-propanyl) silyl) oxy) -1-butyn-1-yl) -7'-methoxy-11 ', 12'-dimethyl-3,4 -Dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazettracyclo [14.7.2.0-3,6-0.0-19, 24 ~] Pentacosa [8,16,18,24] tetraen] -15'-one 1 'in THF (0.700 mL, 0.700 mmol) in a room temperature solution of 13', 13'-dioxide (0.173 g, 0.217 mmol). M tetrabutylammonium fluoride solution was added. The reaction was partitioned between EtOAc and brine, the organic layer was evaporated onto silica gel and purified by flash chromatography (Isco (12 g)) eluting with 25% EtOH: heptane (0: 1 to 1: 0) in EtOAc. (1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7 '-(4-hydroxy-1-butyn-1-yl) -7'-meth Toxy-11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0 ~ 3,6 ~ .0 ~ 19,24 ~] Pentacosa [8,16,18,24] tetraene] -15'-on 13 ', 13'-dioxide and (1S, 3'R , 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7 '-(4-hydroxy-1-butyn-1-yl) -7'-methoxy-11' , 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0 ~ 3,6 ~ .0 ~ 19,24 ~] Pentacosa [8,16,18,24] tetraen] -15'-one 13 ', 13'-dioxide was obtained as a white solid (91 mg, 61 % Yield).

Step 4: (1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-Chloro-7'-methoxy-11 ', 12'-dimethyl-7'-( 4- (4-morpholinyl) -1-butyn-1-yl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [ 1,14] diatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraene] -15'-one 13 ', 13'- Dioxide or (1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-methoxy-11 ', 12'-dimethyl-7'- (4- (4-morpholinyl) -1-butyn-1-yl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diaza tetracyclo [14.7.2.0-3,6-0.0-19,24-] pentacosa [8,16,18,24] tetraene] -15'-one 13 ', 13' Dioxide

(1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7 '-(4-hydroxy-1-butyn-1 in dichloromethane (1.5 mL) -Yl) -7'-methoxy-11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-[20] oxa [13] thia [ 1,14] diatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraene] -15'-one 13 ', 13'- Dioxide and (1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7 '-(4-hydroxy-1-butyn-1-yl)- 7'-methoxy-11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-[20] oxa [13] thia [1,14] Diazatetracyclo [14.7.2.0-3,6-0.0-19,24-] Pentacosa [8,16,18,24] tetraene] -15'-one 13 ', 13'-dioxide (0.057 g , 0.084 mmol) was added triethylamine (0.060 mL, 0.43 mmol) followed by methanesulfonyl chloride (0.035 mL, 0.45 mmol) to give a yellow mixture. After 15 minutes, morpholine (0.075 mL, 0.86 mmol) was added and the reaction stirred for 1 hour. Morpholine (0.035 mL) was added to the reaction and the reaction was stirred overnight at room temperature. The reaction mixture was partitioned between CH 2 Cl 2 and brine, and the aqueous layer was extracted twice with CH 2 Cl 2 and brine. The combined organic layers were dried over Na 2 SO 4, filtered and concentrated under reduced pressure to yield 110 mg of yellow tar. Purification according to the two-step SFC method (Step 1: Cyano column, 20% isopropanol in 20 mM NH ₃ , 80 g / min; Step 2: MSA column, 40% MeOH in 20 mM NH ₃ ) (1S , 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-methoxy-11 ', 12'-dimethyl-7'-(4- (4- Morpholinyl) -1-butyn-1-yl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] dia Jatetracyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ', 13'-dioxide or (1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-methoxy-11 ', 12'-dimethyl-7'-(4- (4 -Morpholinyl) -1-butyn-1-yl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] Diazatetracyclo [14.7.2.0 ~ 3,6 ~ .0 ~ 19,24 ~] Pentacosa [8,16,18,24] tetraene] -15'-one 13 ', 13'-dioxide white crystals Obtained as a sexual solid (6 mg, 10% yield). ¹ H NMR (400 MHz, CD ₂ Cl ₂ ) δ 7.72 (d, J = 8.41 Hz, 1 H), 7.19 (s, 1 H), 7.17 (dd, J = 8.51, 2.25 Hz, 1 H), 7.09 (d, J = 2.15 Hz, 1 H), 6.80-6.95 (m, 2 H), 6.23-6.39 (m, 1 H), 5.52 (d, J = 15.26 Hz, 1 H), 4.39 (d, J = 14.87 Hz, 1H), 4.26-4.34 (m, 1H), 4.01-4.14 (m, 2H), 3.69 (d, J = 14.08 Hz, 1H), 3.58 (t, J = 4.69 Hz, 4 H), 3.26 (d, J = 14.28 Hz, 1 H), 3.12 (s, 3 H), 3.00 (dd, J = 15.16, 10.47 Hz, 1 H), 2.63-2.86 (m, 5 H), 2.51-2.63 (m, 2H), 2.51-2.63 (m, 2H), 2.34-2.48 (m, 5H), 2.11-2.24 (m, 2H), 2.04-2.11 (m, 1H), 1.75-2.03 (m, 6H), 1.59-1.72 (m, 1H), 1.46 (d, J = 7.24 Hz, 3H), 1.39 (t, J = 13.20 Hz, 1H), 1.03 (d, J = 6.65 Hz, 3 H). MS (ESI, cation) m / z 750.3 (M + l) ⁺ .

Example 100013

2-((1S, 3'R, 6'R, 7'R, 11'S, 12'R) -6-chloro-7'-hydroxy-11 ', 12'-dimethyl-13', 13'- Dioxido-15'-oxo-3,4-dihydro-2H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diaza tetracyclo [14.7.2.0-3] , 6 ~ .0 ~ 19,24 ~] pentacosa [16,18,24] trien] -7'-yl) -N, N-dimethylacetamide

To a solution of diisopropylamine (0.19 mL, 1.3 mmol) in THF (1.0 mL) at 0 ° C. was added a solution of N-butyllithium (1.6 M in hexanes, 0.83 mL, 1.3 mmol). The solution was stirred at 0 ° C. for 2 minutes and then dimethyl acetamide (0.12 mL, 1.3 mmol) was added. The reaction was then stirred at 0 ° C. for 7 minutes. Then (1S, 3'R, 6'R, 11'S, 12'R) -6-chloro-11 ', 12'-dimethyl-3,4-dihydro-2H, 7' in THF (1.3 mL). H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6-0.0-19,24-] penta Cosa [16,18,24] triene] -7 ', 15'-dione 13', 13'-dioxide (0.040 g, 0.067 mmol) solution was added and maintained at 0 ° C. for 17 minutes. The reaction was quenched with saturated ammonium chloride solution, acidified with 1 N HCl to pH 2-3 and extracted with EtOAc. The organic phase was washed with brine and dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to give crude product, which was subjected to SFC chromatography (CC4 250 mm x 21 mm column, Phenomenex; 33 g / min MeOH on Thar 200 SFC ( 2 M ammonia as a modifier) + 27 g / min CO ₂ ; Output pressure = 100 bar; Temperature = 40 ° C; Wavelength = 246 nm; DCM: MeOH sample solution in a 1: 1 ratio of 30 mg / mL (2.0 mL ) Is injected into 2.0 mL) to give 2-((1S, 3'R, 6'R, 7'R, 11'S, 12'R) -6-chloro-7'-hydroxy-11 ', 12' -Dimethyl-13 ', 13'-dioxido-15'-oxo-3,4-dihydro-2h-spiro [naphthalene-1,22'-[20] oxa [13] thia [1,14] Diazatetracyclo [14.7.2.0 ~ 3,6 ~ .0 ~ 19,24 ~] Pentacosa [16,18,24] trien] -7'-yl) -n, n-dimethylacetamide first Obtained as diastereomer eluting first (17 mg, 37% yield). ¹ H NMR (400 MHz, Dichloromethane-d2) δ 7.71 (d, J = 8.4 Hz, 1H), 7.16 (dd, J = 2.2, 8.5 Hz, 1H), 7.09 (d, J = 2.2 Hz, 1H) , 7.04-6.98 (m, 2H), 6.97-6.91 (m, 1H), 5.23 (br s, 1H), 4.17-4.06 (m, 3H), 3.68 (d, J = 14.3 Hz, 1H), 3.58 ( d, J = 15.3 Hz, 1H), 3.23 (d, J = 14.3 Hz, 1H), 3.17 (s, 3H), 3.02 (dd, J = 9.7, 15.4 Hz, 1H), 2.97 (s, 3H), 2.84-2.67 (m, 4H), 2.65-2.54 (m, 1H), 2.46 (quin, J = 9.0 Hz, 1H), 2.10-1.97 (m, 2H), 1.96-1.72 (m, 5H), 1.68- 1.42 (m, 5H), 1.39 (d, J = 7.2 Hz, 3H), 1.37-1.35 (m, 1H), 1.35-1.18 (m, 2H), 0.99 (d, J = 6.7 Hz, 3H). MS (ESI, cation) m / z 686.2 (M + l) ⁺ .

Example 100014

(1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-methoxy-7 ', 11', 12'-trimethyl-3,4-di Hydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~ ] Pentacosa [8,16,18,24] tetraene] -15'-on 13 ', 13'-dioxide

Step 1: (1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-7 ', 11', 12'-trimethyl-3, 4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19 , 24 ~] pentacosa [8,16,18,24] tetraene] -15'-on 13 ', 13'-dioxide

(1S, 3'R, 6'R, 8'E, 11'S, 12'R) -6-chloro-11 ', 12'-dimethyl-3,4-dihydro-2H, 7'H, 15' H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6-0.0-19,24-] pentacosa [8, 16,18,24] tetraene] -7 ', 15'-dione 13', 13'-dioxide (200 mg, 0.335 mmol) was dissolved in THF (3.00 mL) and cooled to 0 ° C. To this solution was added a lanthanum (III) -bis (lithium chloride) complex solution (0.6 M in THF, 0.63 mL, 0.34 mmol) and the solution was stirred for 45 minutes. To the solution was added methylmagnesium bromide (3.0 M in diethyl ether solution, 0.50 mL, 1.5 mmol) and warmed to room temperature overnight. Further aliquots of methylmagnesium bromide (3.0 M in diethyl ether solution, 0.502 mL, 1.51 mmol) were added and the reaction stirred for 30 minutes to complete the reaction, followed by saturated ammonium chloride solution. Called. The solution was then acidified to pH 6.5 and extracted with EtOAc (2 x 50 mL). The combined organic layers were then washed with brine (1 x 20 mL) and dried over sodium sulfate. The residue was then purified by chromatography (silica; 20% to 100% EtOAc in hexanes containing 0.3% HOAc) (1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12). 'R) -6-chloro-7'-hydroxy-7', 11 ', 12'-trimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-[20] Oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraen] -15'-one 13 ', 13'-dioxide was obtained as the second eluting diastereomer (124 mg, 60% yield). MS (ESI, cation) m / z 613.1 (M + 1) ⁺ .

Step 2: (1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-methoxy-7 ', 11', 12'-trimethyl-3, 4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19 , 24-] pentacosa [8,16,18,24] tetraene] -15'-on 13 ', 13'-dioxide.

(1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-7 ', 11', 12'-trimethyl-3,4-di Hydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~ ] Pentacosa [8,16,18,24] tetraen] -15'-one 13 ', 13'-dioxide (30 mg, 0.049 mmol) was dissolved in tetrahydrofuran (1.0 mL) and cooled to 0 ° C. . Then sodium hydride (60% dispersion, 20 mg, 0.49 mmol) was added and the resulting slurry was stirred for 20 minutes. Then methyl iodide (0.031 mL, 0.49 mmol) was added and the reaction mixture was stirred for 2.5 h while slowly warming to room temperature. An aliquot of sodium hydride (60% dispersion, 20 mg, 0.49 mmol) and methyl iodide (0.031 mL, 0.49 mmol) was added and the reaction was further stirred for 3.5 hours to complete the reaction. Ammonium chloride was then added dropwise to quench the reaction and the mixture was extracted with EtOAc (2 × 50 mL). The combined organic layers were then washed with brine (1 x 20 mL) and dried over sodium sulfate. The crude product was purified by chromatography (silica; 0% to 50% EtOAc in hexanes) to (1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7 ' -Methoxy-7 ', 11', 12'-trimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] Diazatetracyclo [14.7.2.0-3,6-0.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ', 13'-dioxide was obtained. (29 mg, 95% yield). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.89 (s, 1H), 7.64 (d, J = 8.6 Hz, 1H), 7.27 (dd, J = 2.1, 8.5 Hz, 1H), 7.17 (d, J = 2.0 Hz, 1H), 7.03 (dd, J = 1.5, 8.1 Hz, 1H), 6.89 (d, J = 8.2 Hz, 1H), 6.79 (s, 1H), 5.72 (dd, J = 3.2, 9.3 Hz , 1H), 5.65-5.55 (m, 1H), 4.16-4.08 (m, 1H), 4.07-3.94 (m, 2H), 3.69 (d, J = 14.7 Hz, 1H), 3.59 (d, J = 14.3 Hz, 1H), 3.24 (d, J = 14.3 Hz, 1H), 3.08 (dd, J = 9.6, 14.7 Hz, 1H), 2.94 (s, 3H), 2.84-2.62 (m, 2H), 2.36-1.60 (m, 12H), 1.43-1.36 (m, 1H), 1.33 (d, J = 7.2 Hz, 3H), 1.30 (s, 3H), 0.96 (d, J = 6.7 Hz, 3H). MS (ESI, cation) m / z 627.2 (M + l) ⁺ .

Example 100015

(2S, 3'R, 6'R, 11'S, 12'R, 22'S) -6 ''-chloro-11 ', 12'-dimethyl-3' ', 4' '-dihydro-2''H , 15'H-Dicero [1,4-dioxane-2,7 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19 , 24 ~] pentacosa [16,18,24] triene-22 ', 1' '-naphthalene] -15'-one 13', 13'-dioxide or (2R, 3'R, 6'R, 11'S , 12'R, 22'S) -6 ''-Chloro-11 ', 12'-dimethyl-3' ', 4' '-dihydro-2''H, 15'H-dispiro [1,4- Dioxane-2,7 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [16,18,24 ] Triene-22 ', 1' '-naphthalene] -15'-on 13', 13'-dioxide

Step 1: (1S, 3'R, 6'R, 8'E, 11'S, 12'R) -6-chloro-11 ', 12'-dimethyl-7'-methylidene-3,4-dihydro -2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazettracyclo [14.7.2. ~ 3,6 ~ .0 ~ 19,24 ~] Pentacosa [8,16,18,24] tetraene] -15'-on 13 ', 13'-dioxide

A solution of methyltrimethylphosphonium bromide (1.80 g, 5.0 mmol) in THF (15 mL) was cooled to 0 ° C. N-butyllithium solution (2.5 M in hexanes, 1.8 mL, 4.5 mmol) was added dropwise and the solution was stirred at 0 ° C. for 10 minutes. To this solution (1S, 3'R, 6'R, 11'S, 12'R) -6-chloro-11 ', 12'-dimethyl-3,4-dihydro-2H, 7 in THF (6.0 mL) 'H, 15'H-spiro [naphthalene-1,22'-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] A solution of pentacosa [16,18,24] triene] -7 ', 15'-dione 13', 13'-dioxide (0.30 g, 0.50 mmol) was added dropwise and in an ice bath until the solution remained yellow. Cooled. The solution was stirred at 0 ° C. for 12 minutes. The reaction mixture was added to stirred ice water (20 mL), and acidified with 1 N HCl to pH 2-4. The organic phase was separated and the aqueous phase was extracted with EtOAc (50 mL). The organic phase was washed with brine and dried over magnesium sulfate. The filtrate was concentrated to give crude product. The compound was purified by chromatography (silica; 0% to 50% EtOAc in hexanes containing 0.3% HOAc) (1S, 3'R, 6'R, 8'E, 11'S, 12'R) -6-chloro -11 ', 12'-dimethyl-7'-methylidene-3,4-dihydro-2h, 15'h-spiro [naphthalene-1,22'-[20] oxa [13] thia [1,14 ] Diazatetracyclo [14.7.2.0 ~ 3,6 ~ .0 ~ 19,24 ~] Pentacosa [8,16,18,24] tetraen] -15'-one 13 ', 13'-dioxide (290 mg, 97% yield). MS (ESI, cation) m / z 595.2 (M + H) ⁺ .

Step 2: (1S, 3'R, 6'R, 8'E, 11'S, 12'R) -6-Chloro-7'-hydroxy-7 '-(hydroxymethyl) -11', 12'- Dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0 ^3,6 . 0 ^19,24 ] pentacosa [8,16,18,24] tetraene] -15'-on 13 ', 13'-dioxide

The AD-Mix-alpha mixture (640 mg, 0.43 mmol) was dissolved in a mixture of tert-butanol (10.0 mL) and water (10.0 mL) and cooled to 0 ° C. (1S, 3'R, 6'R, 8'E, 11'S, 12'R) -6-Chloro-11 ', 12'-dimethyl-7'-methylidene-3,4-dihydro-2h, 15'h-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6-0.0-19,24-] pentacosa [ 8,16,18,24] tetraen] -15'-one 13 ', 13'-dioxide (255 mg, 0.428 mmol) was added and the reaction mixture was allowed to slowly warm up to room temperature overnight. An additional 5.0 mL of t-BuOH was added to homogenize the mixture. The reaction was stirred overnight. An additional 320 mg of AD-Mix-alpha mixture was added and the reaction was further stirred for 3 days. 575 mg of sodium sulfite was added at 0 ° C. and stirred for 45 minutes to quench the reaction. The mixture was then extracted twice with EtOAc (25 mL). The combined organic layers were washed with brine (1 x 20 mL) and dried over sodium sulfate. The crude product is then purified by chromatography (silica; 0% to 100% EtOAc in heptanes containing 0.3% HOAc) (1S, 3'R, 6'R, 8'E, 11'S, 12'R). -6-chloro-7'-hydroxy-7 '-(hydroxymethyl) -11', 12'-dimethyl-3,4-dihydro-2h, 15'h-spiro [naphthalene-1,22 ' -[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~]] pentacosa [8,16,18,24] tetraene -15'-one 13 ', 13'-dioxide was obtained (31 mg, 12% yield). MS (ESI, cation) m / z 629.2 (M + H) ⁺ .

Step 3: (1S, 3'R, 6'R, 11'S, 12'R) -7 '-((2-bromoethoxy) methyl) -6-chloro-7'-hydroxy-11', 12 ' -Dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3, 6 ~ .0 ~ 19,24 ~] Pentacosa [16,18,24] triene] -15'-one 13 ', 13'-dioxide

(1S, 3'R, 6'R, 8'E, 11'S, 12'R) -6-Chloro-7'-hydroxy-7 '-(hydroxymethyl) -11', 12'-dimethyl- 3,4-dihydro-2h, 15'h-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6-0.0 ~ 19,24 ~]] pentacosa [8,16,18,24] tetraen] -15'-one 13 ', 13'-dioxide (30.0 mg, 0.048 mmol) was dissolved in THF (1.0 mL) and 0 Cool to C. Sodium hydride (60% dispersion, 19.0 mg, 0.48 mmol) is added, the resulting slurry is stirred for 10 minutes and then 2-bromoethyl trifluoromethanesulfonate (Ark Pharm Inc.) (61 mg, 0.24 mmol ) Was added and the reaction was allowed to slowly warm to room temperature over 45 minutes. Then the reaction was quenched by the slow addition of water (5 mL) and the mixture was extracted with ethyl acetate (2 × 25 mL). The combined organic layers were washed with brine (1 x 15 mL) and then dried over magnesium sulfate. The residue was then purified by chromatography (silica; 0% to 50% EtOAc in hexanes containing 0.3% HOAc) (1S, 3'R, 6'R, 11'S, 12'R) -7'- ((2-bromoethoxy) methyl) -6-chloro-7'-hydroxy-11 ', 12'-dimethyl-3,4-dihydro-2h, 15'h-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [16,18,24] triene] -15 '-On 13', 13'-dioxide was obtained (25 mg, 71% yield). MS (ESI, cation) m / z 739.1 (M + H) ⁺ .

Step 4: (2S, 3'R, 6'R, 11'S, 12'R, 22'S) -6 ''-chloro-11 ', 12'-dimethyl-3' ', 4' '-dihydro-2 'H, 15'H-dicespiro [1,4-dioxane-2,7'-[20] oxa [13] thia [1,14] diazettracyclo [14.7.2.0-3,6]. 0-19,24-] pentacosa [16,18,24] triene-22 ', 1' '-naphthalene] -15'-one 13', 13'-dioxide or (2R, 3'R, 6 ' R, 11'S, 12'R, 22'S) -6 ''-Chloro-11 ', 12'-dimethyl-3' ', 4' '-dihydro-2''H, 15'H-dicespiro [1 , 4-dioxane-2,7 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6-0.0-19,24-] pentacosa [16, 18,24] triene-22 ', 1' '-naphthalene] -15'-on 13', 13'-dioxide

Then (1S, 3'R, 6'R, 11'S, 12'R) -7 '-((2-bromoethoxy) methyl) -6-chloro-7'-hydroxy-11', 12'- Dimethyl-3,4-dihydro-2h, 15'h-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] Pentacosa [16,18,24] triene] -15'-13 ', 13'-dioxide (25.0 mg, 0.034 mmol) is dissolved in DMF (0.5 mL) and hydrogenated Sodium (60% dispersion, 19 mg, 0.48 mmol) was added. The mixture was then heated to 85 ° C. for 10 minutes. The reaction mixture was then cooled to room temperature and quenched by dropwise addition of water (5 mL). The mixture was extracted twice with ethyl acetate (20 mL). The combined organic layers were washed with 1 N LiCl solution (1 x 15 mL) and brine (1 x 10 mL) and dried over magnesium sulfate. The crude product was purified by chromatography (silica; 0% to 50% EtOAc in hexanes containing 0.3% HOAc) (2S, 3'R, 6'R, 11'S, 12'R, 22'S) -6 ''- Chloro-11 ', 12'-dimethyl-3'',4''-dihydro-2''h,15'h-dispiro[1,4-dioxane-2,7'-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [16,18,24] triene-22 ', 1''-naphthalene ] -15'-one 13 ', 13'-dioxide or (2R, 3'R, 6'R, 11'S, 12'R, 22'S) -6''-chloro-11',12'-dimethyl-3 ``, 4 ''-dihydro-2''h, 15'h-dispiro [1,4-dioxane-2,7 '-[20] oxa [13] thia [1,14] diazate Cyclo [14.7.2.0 ~ 3,6 ~ .0 ~ 19,24 ~] Pentacosa [16,18,24] triene-22 ', 1''-naphthalene]-15'-one13',13'- Dioxide was obtained (14 mg, 45% yield). ¹ H NMR (400 MHz, MeOH) δ 7.73 (d, J = 8.4 Hz, 1H), 7.17 (dd, J = 2.2, 8.4 Hz, 1H), 7.13-7.08 (m, 2H), 7.02 (d, J = 1.6 Hz, 1H), 6.92 (d, J = 8.0 Hz, 1H), 4.08 (s, 2H), 4.06-4.01 (m, 1H), 3.76 (d, J = 11.9 Hz, 2H), 3.73-3.59 ( m, 4H), 3.58-3.49 (m, 1H), 3.46-3.38 (m, 1H), 3.23-3.15 (m, 1H), 3.10 (dd, J = 9.1, 15.4 Hz, 1H), 2.86-2.68 ( m, 2H), 2.62-2.50 (m, 1H), 2.11-2.03 (m, 1H), 1.96-1.84 (m, 3H), 1.76-1.51 (m, 7H), 1.49-1.40 (m, 1H), 1.36 (d, J = 7.0 Hz, 3H), 1.34-1.27 (m, 2H), 1.23-1.19 (m, 2H), 1.01 (d, J = 6.8 Hz, 3H). MS (ESI, cation) m / z 657.2 (M + H) ⁺ .

Example 100017

(1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-11 ', 12'-dimethyl-7'-(4- ( 4-morpholinyl) -1-butyn-1-yl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14 ] Diazatetracyclo [14.7.2.0-3,6-0.0-19,24-] pentacosa [8,16,18,24] tetraene] -15'-one 13 ', 13'-dioxide or ( 1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-11 ', 12'-dimethyl-7'-(4- (4-morpholinyl) -1-butyn-1-yl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1, 14] diaza tetracyclo [14.7.2.0 to 3,6 to .0 to 19,24 to] pentacosa [8,16,18,24] tetraene] -15'-on 13 ', 13'-dioxide

To a cold solution (-78 ° C.) of 4- (but-3-yn-1-yl) morpholine (0.163 g, 1.171 mmol) in tetrahydrofuran (3 mL) 2.5 M in toluene (0.400 mL, 1.00 mmol) Butyllithium solution was added dropwise through a syringe. After 45 minutes, (1S, 3'R, 6'R, 8'E, 11'S, 12'R) -6-chloro-11 ', 12'-dimethyl-3,4-di in THF (1 mL) Hydro-2H, 7'H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ A solution of 19,24-] pentacosa [8,16,18,24] tetraene] -7 ', 15'-dione 13', 13'-dioxide (0.100 g, 0.167 mmol) was added dropwise. After 1 hour, the reaction was quenched with saturated NH 4 Cl (3 mL) and the mixture was allowed to warm to room temperature. The mixture was extracted three times with dichloromethane and the combined organic layers were washed with brine and then dried over Na 2 SO 4. The solution was filtered and the filtrate was concentrated under reduced pressure to give an orange oil. Crude was purified using preparative SFC (Waters Thar 200; Cyano column (21.1x250 mm, 5 μιη) with 18% methanol (20 mM NH ₃ ), 82% carbon dioxide; flow rate = 95 mL / min, column temperature = 40 ° C, (1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro, the first eluting diastereoisomer purified by pressure = 100 bar, detected at 220 nm) -7'-hydroxy-11 ', 12'-dimethyl-7'-(4- (4-morpholinyl) -1-butyn-1-yl) -3,4-dihydro-2H, 15 ' H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6-0.0-19,24-] pentacosa [8, 16,18,24] tetraen] -15'-on 13 ', 13'-dioxide or (1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6- Chloro-7'-hydroxy-11 ', 12'-dimethyl-7'-(4- (4-morpholinyl) -1-butyn-1-yl) -3,4-dihydro-2H, 15 'H-spiro [naphthalene-1,22'-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6-0.0-19,24-] pentacosa [8 , 16,18,24] tetraene] -15'-on 13 ', 13'-dioxide as a white solid It was (32 mg, 26%). ¹ H NMR (400 MHz, CD ₂ Cl ₂ ) δ 7.72 (d, J = 8.41 Hz, 1 H), 7.13-7.24 (m, 2 H), 7.09 (d, J = 1.96 Hz, 1 H), 6.83 -6.96 (m, 2H), 6.25-6.41 (m, 1H), 5.75 (d, J = 15.26 Hz, 1H), 4.38 (d, J = 15.06 Hz, 1H), 4.29 (q, J = 7.37 Hz, 1 H), 3.97-4.13 (m, 2 H), 3.69 (d, J = 14.08 Hz, 1 H), 3.58 (t, J = 4.69 Hz, 4 H), 3.26 (d, J = 14.28 Hz, 1 H), 3.00 (dd, J = 15.26, 10.37 Hz, 1 H), 2.47-2.87 (m, 7 H), 2.29-2.46 (m, 5 H), 1.80-2.21 (m, 9 H ), 1.61-1.72 (m, 1H), 1.44 (d, J = 7.24 Hz, 3H), 1.33-1.41 (m, 1H), 1.03 (d, J = 6.85 Hz, 3H). MS (ESI, cation) m / z 736.2 (M + l) ⁺ .

Example 100018

(1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-11 ', 12'-dimethyl-7'-(3- ( 4-morpholinyl) -1-propyn-1-yl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1, 14] diaza tetracyclo [14.7.2.0-3,6-0.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ', 13'-dioxide or (1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-Chloro-7'-hydroxy-11 ', 12'-dimethyl-7'-(3 -(4-morpholinyl) -1-propyn-1-yl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [ 1,14] diatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraene] -15'-one 13 ', 13'- Dioxide

A butyllithium solution (-78 ° C.) in a cold solution (-78 ° C.) of 4- (prop-2-yn-1-yl) morpholine (0.170 mL, 1.35 mmol, Ark Pharm, Inc.) in tetrahydrofuran (3 mL) 2.5 M in toluene, 0.500 mL, 1.25 mmol) was added dropwise via syringe. After 45 minutes, (1S, 3'R, 6'R, 8'E, 11'S, 12'R) -6-chloro-11 ', 12'-dimethyl-3,4-di in THF (1 mL) Hydro-2H, 7'H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ A solution of 19,24-] pentacosa [8,16,18,24] tetraene] -7 ', 15'-dione 13', 13'-dioxide (0.100 g, 0.167 mmol) was added dropwise. After 1 hour, the reaction was quenched with saturated NH 4 Cl (3 mL) and the mixture was allowed to warm to room temperature. The mixture was extracted three times with DCM, and the combined organic layers were washed with brine and then dried over Na 2 SO 4. The solution was filtered and the filtrate was concentrated under reduced pressure to give a yellow oil. The crude was purified using preparative SFC (Premier (2 x 25 cm); 50% methanol / CO ₂ , 100 bar; 50 mL / min, 254 nm) to elute the first eluting isomer, (1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-11 ', 12'-dimethyl-7'-(3- (4-morpholinyl)- 1-propyn-1-yl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazettracyclo [ 14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ', 13'-dioxide or (1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-11 ', 12'-dimethyl-7'-(3- (4-morpholinyl ) -1-propyn-1-yl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazate Cyclo [14.7.2.0-3,6-.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ', 13'-dioxide was obtained as a solid ( 40 mg, 33% yield). ¹ H NMR (400 MHz, CD ₂ Cl ₂ ) δ 7.71 (d, J = 8.41 Hz, 1 H), 7.12-7.23 (m, 2 H), 7.09 (d, J = 2.15 Hz, 1 H), 6.84 -6.97 (m, 2H), 6.22-6.40 (m, 1H), 5.78 (d, J = 14.87 Hz, 1H), 4.25 (d, J = 14.67 Hz, 2H), 4.07 (s, 2 H), 3.70 (d, J = 14.28 Hz, 1 H), 3.59-3.66 (m, 4 H), 3.56 (s, 2 H), 3.25 (d, J = 14.08 Hz, 1 H), 3.02 (dd , J = 15.16, 10.47 Hz, 1 H), 2.67-2.89 (m, 2 H), 2.51-2.65 (m, 5 H), 2.33-2.49 (m, 1 H), 2.02-2.16 (m, 4 H ), 1.76-2.01 (m, 7 H), 1.62-1.73 (m, 1 H), 1.43 (d, J = 7.04 Hz, 3 H), 1.34-1.41 (m, 1 H), 1.04 (d, J = 6.46 Hz, 3 H). MS (ESI, cation) m / z 722.2 (M + l) ⁺ .

Example 100019

(1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-11 ', 12'-dimethyl-7'-((2R) -4-methyl-3-oxo-2-morpholinyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14 ] Diazatetracyclo [14.7.2.0-3,6-0.0-19,24-] pentacosa [8,16,18,24] tetraene] -15'-one 13 ', 13'-dioxide or ( 1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-11 ', 12'-dimethyl-7'-((2S)- 4-methyl-3-oxo-2-morpholinyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] Diazatetracyclo [14.7.2.0-3,6-0.0-19,24-] Pentacosa [8,16,18,24] tetraene] -15'-one 13 ', 13'-dioxide or (1S , 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-11 ', 12'-dimethyl-7'-((2S) -4-methyl-3-oxo-2-morpholinyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14 ] Diazatetracyclo [14.7.2.0 ~ 3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraene] -15'-one 13 ', 1 3'-dioxide or (1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-11 ', 12'-dimethyl- 7 '-((2R) -4-methyl-3-oxo-2-morpholinyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-[20] oxa [ 13] thia [1,14] diatetracyclo [14.7.2.0-3,6-0.0-19,24-] pentacosa [8,16,18,24] tetraene] -15'-one 13 ' , 13'-dioxide

To a solution of diisopropylamine (1.183 mL, 8.44 mmol) in tetrahydrofuran (4.22 mL) at 0 ° C. was added butyllithium (2.5 M in hexanes, 3.38 mL, 8.44 mmol) for 3 minutes. The solution was then cooled to -78 ° C. 4-methyl-morpholin-3-one (0.887 mL, 8.44 mmol) was added dropwise and the solution was stirred for 1 hour. (1S, 3'R, 6'R, 8'E, 11'S, 12'R) -6-chloro-11 ', 12'-dimethyl-3,4-dihydro-2H, in 0.5 mL of THF solution, 7'H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~ ] Pentacosa [8,16,18,24] tetraene] -7 ', 15'-dione 13', 13'-dioxide (0.252 g, 0.422 mmol) was added dropwise. After completion, saturated aqueous ammonium chloride solution was added. 1 N HCl was added until the pH reached 2-3, and the solution was extracted with EtOAc. The organic extract was washed with saturated NaCl, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude product was adsorbed onto a silica gel plug and purified by chromatography through a Biotage SNAP ultra silica gel column (50 g) eluting with EtOAc: EtOH (3: 1) in a gradient of 10% to 100%. . Preparative SFC using Me-sulfon achiral column (21 × 150 mm, 5 μm; 60% methanol with 20 mM NH ₃ , flow rate 60 mL / min, column temperature 40 ° C., pressure 100 bar, 220 nm) Further purified. The third eluting isomer is isolated to give (1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-11 ', 12'-die Methyl-7 '-((2R) -4-methyl-3-oxo-2-morpholinyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-[20] Oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraen] -15'-one 13 ', 13'-dioxide or (1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-11', 12'-dimethyl -7 '-((2S) -4-methyl-3-oxo-2-morpholinyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraen] -15'-one 13 ', 13'-dioxide or (1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-11', 12'-die Methyl-7 '-((2S) -4-methyl-3-oxo-2-morpholinyl) -3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22'-[20] Oxa [13] thia [1,14] diaza tetracyclo [14.7.2.0 ~ 3,6 ~ .0 ~ 19,24 Pentacosa [8,16,18,24] tetraen] -15'-on 13 ', 13'-dioxide or (1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-Chloro-7'-hydroxy-11 ', 12'-dimethyl-7'-((2R) -4-methyl-3-oxo-2-morpholinyl) -3,4 -Dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazettracyclo [14.7.2.0-3,6-0.0-19, 24 ~] pentacosa [8,16,18,24] tetraen] -15'-one was obtained. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 0.92 (d, J = 6.06 Hz, 3 H) 1.02 (br. S., 2 H) 1.36 (t, J = 12.72 Hz, 1 H) 1.61 (br s., 3 H) 1.87 (br. s., 3 H) 1.92-2.13 (m, 3 H) 2.25 (d, J = 7.63 Hz, 1 H) 2.62-2.79 (m, 2 H) 2.84 (s , 3 H) 2.86-3.06 (m, 3 H) 3.29 (br. S., 1 H) 3.55 (d, J = 13.50 Hz, 1 H) 3.71 (br. S., 1 H) 3.79-4.01 (m , 4 H) 4.10 (d, J = 13.30 Hz, 1 H) 4.26 (br. S., 1 H) 5.33 (br. S., 1 H) 5.71 (d, J = 15.45 Hz, 1 H) 6.17 ( br.s., 1H) 6.67-6.84 (m, 1H) 6.98-7.41 (m, 4H) 7.65 (d, J = 8.61 Hz, 1H). MS (ESI, cation) m / z 712.2 (M + l) ⁺ .

Example 100020

1-((1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-11 ', 12'-dimethyl-13', 13 '-Dioxido-15'-oxo-3,4-dihydro-2H-spiro [naphthalene-1,22'-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0 ~ 3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraen] -7'-yl) -N, N-dimethylmethanesulfonamide or 1-((1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-11 ', 12'-dimethyl-13', 13'-dioxy Fig. 15'-Oxo-3,4-dihydro-2H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] Pentacosa [8,16,18,24] tetraen] -7'-yl) -N, N-dimethylmethanesulfonamide

To a solution of N, N-dimethylmethanesulfonamide (206 mg, 1.68 mmol) in 2-methyltetrahydrofuran (4 mL) at 0 ° C. add n-butyllithium (1.6 M in hexane, 0.67 mL, 1.7 mmol). Was added and the reaction stirred at 0 ° C. for 5 minutes. (1S, 3'R, 6'R, 8'E, 11'S, 12'R) -6-chloro-11 ', 12'-dimethyl-3,4- in 2-methyltetrahydrofuran (1 mL) Dihydro-2H, 7'H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraene] -7 ', 15'-dione 13', 13'-dioxide (100 mg, 0.167 mmol) was added at low temperature, 15 After minutes, quenched with aqueous saturated NH ₄ Cl (50 mL), brine (50 mL) and EtOAc (100 mL). The organic layer was separated, dried (Na ₂ SO ₄ ), filtered and concentrated on silica. Purification by silica gel chromatography (0% to 100% EtOAc in heptane containing 0.3% AcOH) 1-((1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) ) -6-chloro-7'-hydroxy-11 ', 12'-dimethyl-13', 13'-dioxido-15'-oxo-3,4-dihydro-2H-spiro [naphthalene-1 , 22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetra N] -7'-yl) -N, N-dimethylmethanesulfonamide and 1-((1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro- 7'-hydroxy-11 ', 12'-dimethyl-13', 13'-dioxido-15'-oxo-3,4-dihydro-2H-spiro [naphthalene-1,22 '-[20 ] Oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraene] -7'- Il) -N, N-dimethylmethanesulfonamide was obtained as an isomer mixture (70 mg, 0.10 mmol, 58% yield). The mixture was separated by preparative SFC chromatography (column: Welko-O1 250 mm x 21 mm column, mobile phase: 65:35 (A: B) isosolvent, A: liquid CO ₂ , B: methanol (20 mM NH ₃ ), flow rate: Purification with 70 g / min, column temperature: 40 ° C., detection: UV at 220 nm), the first eluting isomer 1-((1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-Chloro-7'-hydroxy-11 ', 12'-dimethyl-13', 13'-dioxido-15'-oxo-3,4-dihydro-2H-spiro [ Naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18, 24] tetraen] -7'-yl) -N, N-dimethylmethanesulfonamide or 1-((1S, 3'R, 6'R, 7'R, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-11 ', 12'-dimethyl-13', 13'-dioxido-15'-oxo-3,4-dihydro-2H-spiro [naphthalene-1, 22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0-3,6 ~ .0 ~ 19,24 ~] pentacosa [8,16,18,24] tetraene ] -7'-yl) -N, N-dimethylmethanesulfonamide was isolated (10 mg, 0.014 mmol, 8%). Yield). ¹ H NMR (400 MHz, Chloroform-d) δ 7.69 (d, J = 8.41 Hz, 1H), 7.17 (dd, J = 2.25, 8.51 Hz, 1H), 7.09 (d, J = 2.15 Hz, 1H), 6.94 (s, 2H), 6.87 (s, 1H), 5.68-5.80 (m, 2H), 4.00-4.22 (m, 4H), 3.67-3.83 (m, 2H), 3.57 (br d, J = 14.48 Hz , 1H), 3.20-3.32 (m, 2H), 3.05-3.16 (m, 1H), 2.96 (s, 6H), 2.89-2.93 (m, 1H), 2.69-2.83 (m, 2H), 2.38-2.50 (m, 1H), 2.03-2.17 (m, 3H), 1.85-2.02 (m, 3H), 1.72-1.84 (m, 2H), 1.58-1.70 (m, 2H), 1.46 (d, J = 7.24 Hz , 3H), 1.32-1.41 (m, 1H), 1.06 (d, J = 6.06 Hz, 3H). Exchangeable protons were not observed. MS (ESI, cation) m / z 720.2 (M + H) ⁺ .

Table 2 lists the compounds prepared by the general methods presented herein.

General Synthesis of Intermediates

N-methyl-2-morpholinoethanamine

Step 1: tert-butyl (2-morpholinoethyl) carbamate

Two drum vials were filled with di-t-butyldicarbonate (0.459 mL, 2.000 mmol), magnetic stir bar, and indium (III) chloride (4.42 mg, 0.020 mmol). Then, 4- (2-aminoethyl) morpholine (0.262 mL, 2 mmol) was added to the stirred solution. After 1 h the solution was diluted with EtOAc (2 mL). Water (3 mL) was added and the layers partitioned. The organic layer was washed with water (2 × 5 mL), dried over MgSO ₄ , filtered and concentrated to give tert-butyl (2-morpholinoethyl) carbamate as a clear oil. The material continued to be used without further purification.

Step 2: N-methyl-2-morpholinoethanamine

A 125 mL three neck flask with a stir bar was heated with a heat gun under vacuum. Under positive pressure nitrogen, a reflux condenser was attached to the middle neck. The flask was charged with tetrahydrofuran (25.00 mL) and lithium aluminum hydride (2M solution in THF, 0.84 mL, 20 mmol), and tert-butyl (2-morpholinoethyl) carbamate (0.46 g, 2 mmol) It was added as a solution in THF (8 mL) and the resulting homogeneous mixture was heated to reflux for 18 h. The reaction mixture was cooled to 0 ° C. in an ice bath and quenched with sodium sulfate decahydrate. The resulting mixture was filtered through celite and rinsed with THF. The filtrate was concentrated to give N-methyl-2-morpholinoethanamine, which was used without further purification.

(3R, 3S) -1-cyclobutyl-3-methylhex-5-ene-2-sulfonamide

Step 1: (R) -pent-4-en-2-yl 4-methylbenzenesulfonate

To a solution of vinylmagnesium bromide (226 g, 1722 mmol, 1.0 M in THF) was added CuI (29.5 g, 155 mmol, 0.09 equiv) in THF (200 mL) at -40 ° C. The reaction mixture was stirred for 30 minutes, and then (R) -2-methyloxirane (100 g, 1722 mmol) in THF (500 mL) was added dropwise at the same temperature. The resulting reaction mixture was stirred at -40 ° C for 1 hour. After the reaction was complete (monitored by TLC), triethylamine (261 g, 2583 mmol) was added at -40 ° C. After 30 minutes, a cold solution of p-toluene sulfonyl chloride (427 g, 2238 mmol) in THF (1000 mL) was slowly added to the reaction mixture at the same temperature and stirred at ambient temperature for 16 hours. After the reaction was complete (monitored by TLC), the reaction mixture was quenched with 1.5 N HCl solution until pH 3.0. The resulting reaction mixture was filtered through a pad of celite, the layers were separated and the aqueous layer was extracted again with ethyl acetate (2 x 2000 mL). The combined organic layers were washed with water (800 mL) and brine (500 mL), dried over Na ₂ S0 ₄ and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel; 230-400 mesh) using 1% to 2% ethyl acetate in petroleum ether to give (R) -pent-4-en-2-yl 4-methylbenzene Sulfonate was obtained as a colorless liquid (207 g, 50% yield). ¹ H NMR (300 MHz, Chloroform-d) δ 7.83-7.75 (m, 2H), 7.37-7.31 (m, 2H), 5.69-5.52 (m, 1H), 5.09-5.04 (m, 1H), 5.01 ( t, J = 1.3 Hz, 1H), 4.65 (h, J = 6.3 Hz, 1H), 2.45 (s, 3H), 2.37-2.22 (m, 2H), 1.26 (d, J = 6.3 Hz, 3H).

Step 2: (S) -N, N-bis (4-methoxybenzyl) -2-methylpent-4-ene-1-sulfonamide

To a stirred solution of N, N-bis (4-methoxybenzyl) methanesulfonamide (207 g, 617 mmol) in THF (2000 mL) n-BuLi (321 mL, 802 mmol, 2.5 M in hexanes at -78 ° C). ) Was added. The resulting reaction mixture was stirred for 1 h at the same temperature, followed by (R) -pent-4-en-2-yl 4-methylbenzenesulfonate (206 g, 858 mmol) in THF (400 mL). It was added dropwise at ℃. The reaction mixture was warmed to room temperature and stirred for 16 hours. After the reaction was completed (monitored by TLC), the reaction mixture was quenched with saturated ammonium chloride solution, the layers were separated and the aqueous layer was extracted with ethyl acetate (2 x 2000 mL). The combined organic layers were washed with water (1000 mL) and brine (600 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel; 230-400 mesh) using 2% -4% ethyl acetate in petroleum ether to give (S) -N, N-bis (4-methoxybenzyl) -2. -Methylpent-4-ene-1-sulfonamide was obtained as a colorless liquid (105 g, 42% yield). ¹ H NMR (400 MHz, Chloroform-d) δ 7.25-7.20 (m, 4H), 6.92-6.85 (m, 4H), 5.70 (ddt, J = 17.2, 10.2, 7.1 Hz, 1H), 5.12-4.98 ( m, 2H), 4.32-4.19 (m, 4H), 3.83 (s, 6H), 2.90-2.80 (m, 1H), 2.66-2.55 (m, 1H), 2.27-2.17 (m, 1H), 2.17- 2.02 (m, 2H), 1.11 (d, J = 6.7, 3H).

Step 3: (3S) -1-cyclobutyl-N, N-bis (4-methoxybenzyl) -3-methylhex-5-ene-2-sulfonamide

-78 ° C in a stirred solution of (S) -N, N-bis (4-methoxybenzyl) -2-methylpent-4-ene-1-sulfonamide (40 g, 99 mmol) in THF (400 mL) N-butyllithium (86.73 mL, 139 mmol, 1.6 M in hexane) was added. The reaction mixture was stirred at the same temperature for 20 minutes. (Bromomethyl) cyclobutane (59.1 g, 396 mmol) was added dropwise at the same temperature and stirred for 30 minutes. The resulting reaction mixture was warmed to ambient temperature and stirred for 16 hours. After the reaction was complete (monitored by TLC), the reaction mixture was quenched with the contained ammonium chloride solution, the layers were separated and the aqueous layer was extracted with ethyl acetate (2 x 400 mL). The combined organic layers were washed with water (100 mL) and brine (100 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel; 230-400 mesh) using 2% -4% ethyl acetate in petroleum ether as eluent to give (3S) -1-cyclobutyl-N, N-bis ( 4-methoxybenzyl) -3-methylhex-5-ene-2-sulfonamide was obtained as a colorless liquid (33 g, 71% yield). ¹ H NMR (300 MHz, Chloroform-d) δ 7.30-7.16 (m, 4H), 6.92-6.80 (m, 4H), 5.13-4.95 (m, 2H), 4.40-4.20 (m, 4H), 3.81 ( s, 6H), 2.87-2.63 (m, 2H), 2.16-1.72 (m, 6H), 1.65-1.24 (m, 6H), 1.15-0.81 (m, 3H).

Step 4: (3S) -1-cyclobutyl-3-methylhex-5-ene-2-sulfonamide

(3S) -1-cyclobutyl-N, N-bis (4-methoxybenzyl) -3-methylhex-5-ene-2-sulfonamide (33 g, 70.0 mmol) in a stirred solution of anisole (33) mL) and TFA (33 mL) were added at 0 ° C. The resulting reaction mixture was heated to 40 ° C. for 16 hours. After the reaction is complete (monitored by TLC), the volatiles are removed in vacuo and subjected to flash column chromatography (silica gel; 230-400 mesh) using 15% to 20% ethyl acetate in petroleum ether as eluent. The material was purified to give (3S) -1-cyclobutyl-3-methylhex-5-ene-2-sulfonamide, HPLC [column Sunfire C18 (250 mm x 19 mm) 5 μιη, in water and acetonitrile 0.1% formic acid, 90 mg / injection, ELSD detector, run time 35 minutes] to give (3S) -1-cyclobutyl-3-methylhex-5-ene-2-sulfonamide as a colorless liquid ( 10.3 g, 64% yield). MS (ESI, anion) m / z 230 (MH) ⁻ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 6.78 (d, J = 9.1 Hz, 2H), 5.73 (tdd, J = 12.4, 10.1, 6.5 Hz, 1H), 5.05 (tt, J = 17.7, 4.5 Hz, 2H), 2.70-2.54 (m, 2H), 2.30 (p, J = 7.1 Hz, 1H), 2.00 (dq, J = 26.6, 7.3 Hz, 4H), 1.90-1.72 (m, 3H), 1.58 (dtt, J = 26.6, 17.4, 8.5 Hz, 3H), 0.94 (ddd, J = 14.1, 7.1, 2.1 Hz, 3H).

1- (but-2-yn-1-yl) piperazin-2-one

Step 1: tert-butyl 4- (but-2-yn-1-yl) -3-oxopiperazine-1-carboxylate

To a cold slurry (0 ° C.) of 60% sodium hydride dissolved in mineral oil (0.600 g, 15.00 mmol) in THF (40 mL) 1-Boc-3-oxopipe in N, N-dimethylformamide (10 mL) A solution of lazine (2.0 g, 9.99 mmol; Combi-Blocks, San Diego, CA) was added. After the addition was complete, the reaction was allowed to warm to room temperature for 30 minutes. The mixture was cooled to 0 ° C. and treated with 1-bromo-2-butyene (1.2 mL, 13.71 mmol). The reaction was allowed to warm to room temperature for 30 minutes. The reaction was quenched with saturated NH 4 Cl solution, partitioned between EtOAc / brine and the aqueous layer was extracted three times with EtOAc. The combined organic layers were dried over Na 2 SO 4, filtered, and the filtrate was concentrated under reduced pressure to give tert-butyl 4- (but-2-yl-1-yl) -3-oxopiperazine-1-carboxylate as a light brown liquid.

Step 2: 1- (but-2-yn-1-yl) piperazin-2-one

Trifluoroacetic acid (10) in a room temperature solution of tert-butyl 4- (but-2-yn-1-yl) -3-oxopiperazine-1-carboxylate (2.52 g, 9.99 mmol) in DCM (40 mL) mL, 135 mmol) was added via syringe. After 1 hour, the solvent was removed in vacuo and the residue was dissolved in DCM. The solution was added to a Si-propylsulfonic acid solution and eluted with DCM, MeOH followed by 2 M NH ₃ in MeOH to brown 1- (but-2-yn-1-yl) piperazin-2-one Obtained as an oil (1.269 g, 83% yield). ¹ H NMR (400 MHz, CDCl 3) δ 4.20 (q, J = 2.41 Hz, 2 H), 3.52 (s, 2 H), 3.42 (t, J = 5.48 Hz, 2 H), 3.12 (t, J = 5.58 Hz, 2 H), 1.81 (t, J = 2.45 Hz, 3 H).

The intermediates shown in Table 3 below were prepared in a similar manner as described above for 1- (but-2-yn-1-yl) piperazin-2-one.

1- (2-morpholinoethyl) piperazin-2-one

Step 1: tert-butyl 4- (2-morpholinoethyl) -3-oxopiperazine-1-carboxylate

1-boc-3-oxopiperazine (2.0 g, 9.99 mmol; Combi-Blocks, San Diego, CA), THF (25 mL), tetrabutylammonium bromide (0.620 g, 1.923 mmol) and potassium hydroxide (1.42 g) , 25.3 mmol), were added as a solid to 4- (2-bromoethyl) morpholine hydrobromide (2.78 g, 10.11 mmol; Combi-Blocks, San Diego, CA). After stirring at room temperature overnight, the mixture is filtered, the filtrate is evaporated onto silica gel and flash chromatography (Isco, eluting with 2 M NH ₃ : CH ₂ Cl _{2 (} 0: 1 → 1: 9) in MeOH). (80 g)) was purified to give tert-butyl 4- (2-morpholinoethyl) -3-oxopiperazine-1-carboxylate as a solid (1.923 g, 61% yield). MS (ESI, cation) m / z 314.3 (M + l) ⁺ .

Step 2: 1- (2-morpholinoethyl) piperazin-2-one

To a room temperature solution of tert-butyl 4- (2-morpholinoethyl) -3-oxopiperazine-1-carboxylate (1.84 g, 5.87 mmol) in DCM (15 mL) was added trifluoroacetic acid (5 mL). Added. After 3 hours, the solvent was removed under reduced pressure, the residue was dissolved in DCM and added on a Si-propylsulfonic acid plug, and the plug was added with 2 M NH3 / DCM in MeOH / DCM: MeOH in a 1: 1 ratio. Washed. Fractions containing the desired product were concentrated under reduced pressure to give 1- (2-morpholinoethyl) piperazin-2-one as a yellow oil (1.52 g). MS (ESI, cation) m / z 214.1 (M + l) ⁺ .

(2S, 3S) -3-methyl-1-phenylhex-5-ene-2-sulfonamide and (2R, 3S) -3-methyl-1-phenylhex-5-ene-2-sulfonamide

Step 1: (R) -pent-4-en-2-yl 4-methylbenzenesulfonate

To a solution of vinylmagnesium bromide (226 g, 1722 mmol, 1.0 M in THF), CuI (29.5 g, 155 mmol) in THF (200 mL) was added at -40 ° C. The reaction mixture was stirred for 30 minutes, then a cold solution of (R) -2-methyloxirane (100 g, 1722 mmol) in THF (500 mL) was added dropwise at the same temperature. The resulting reaction mixture was stirred at -40 ° C for 1 hour. After the reaction was complete (monitored by TLC), triethylamine (261 g, 2583 mmol) was added at -40 ° C. After 30 minutes, a cold solution of p-toluene sulfonyl chloride (427 g, 2238 mmol) in THF (1000 mL) was slowly added to the reaction mixture at the same temperature and stirred at ambient temperature for 16 hours. After the reaction was complete (monitored by TLC), the reaction mixture was quenched with 1.5 N HCl solution until pH 3.0. The resulting reaction mixture was filtered through a pad of celite, the layers were separated and the aqueous layer was extracted again with ethyl acetate (2 x 2000 mL). The combined organic layers were washed with water (800 mL) and brine (500 mL), dried over Na ₂ S0 ₄ and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel; 230-400 mesh) using 1% to 2% ethyl acetate in petroleum ether to give (R) -pent-4-en-2-yl 4-methylbenzene Sulfonate was obtained as a colorless liquid (207 g, 50% yield). ¹ H NMR (300 MHz, Chloroform- d ) δ 7.83-7.75 (m, 2H), 7.37-7.31 (m, 2H), 5.69-5.52 (m, 1H), 5.09-5.04 (m, 1H), 5.01 ( t, J = 1.3 Hz, 1H), 4.65 (h, J = 6.3 Hz, 1H), 2.45 (s, 3H), 2.37-2.22 (m, 2H), 1.26 (d, J = 6.3 Hz, 3H).

Step 2: (S) -N, N-bis (4-methoxybenzyl) -2-methylpent-4-ene-1-sulfonamide

N-BuLi (321 mL, 802 mmol, 2.5 M in hexane) to a stirred solution of N, N-bis (4-methoxybenzyl) methanesulfonamide (207 g, 617 mmol, 1.0 equiv) in THF (2000 mL) Was added at -78 ° C. The resulting reaction mixture was stirred for 1 h at the same temperature, followed by (R) -pent-4-en-2-yl 4-methylbenzenesulfonate (206 g, 858 mmol) in THF (400 mL). It was added dropwise at ℃. The reaction mixture was raised to ambient temperature and stirred for 16 hours. After the reaction was complete (monitored by TLC), the reaction mixture was quenched with saturated ammonium chloride solution, the layers were separated and the aqueous layer was extracted with ethyl acetate (2 x 2000 mL). The combined organic layers were washed with water (1000 mL) and brine (600 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel; 230-400 mesh) using 2% -4% ethyl acetate in petroleum ether to give (S) -N, N-bis (4-methoxybenzyl) -2. -Methylpent-4-ene-1-sulfonamide was obtained as a colorless liquid (105 g, 42.2% yield). ¹ H NMR (400 MHz, Chloroform- d ) δ 7.25-7.20 (m, 4H), 6.92-6.85 (m, 4H), 5.70 (ddt, J = 17.2, 10.2, 7.1 Hz, 1H), 5.12-4.98 ( m, 2H), 4.32-4.19 (m, 4H), 3.83 (s, 6H), 2.90-2.80 (m, 1H), 2.66-2.55 (m, 1H), 2.27-2.17 (m, 1H), 2.17- 2.02 (m, 2H), 1.11 (d, J = 6.7, 3H).

Step 3: (2S, 3S) -N, N-bis (4-methoxybenzyl) -3-methyl-1-phenylhex-5-ene-2-sulfonamide and (2R, 3S) -N, N- Bis (4-methoxybenzyl) -3-methyl-1-phenylhex-5-ene-2-sulfonamide

N-butyl in a stirred solution of (S) -N, N-bis (4-methoxybenzyl) -2-methylpent-4-ene-1-sulfonamide (65 g, 161 mmol) in THF (650 mL) Lithium (140.9 mL, 226 mmol, 1.6 M in hexanes) was added at -78 ° C. The reaction mixture was stirred at the same temperature for 20 minutes. (Bromomethyl) benzene (110 g, 644 mmol) was added dropwise at the same temperature and stirred at -78 ° C for 30 minutes. The resulting reaction mixture was warmed to ambient temperature and stirred for 1 hour. After the reaction was completed (monitored by TLC), the reaction mixture was quenched with saturated ammonium chloride solution, the layers were separated and the aqueous layer was extracted with ethyl acetate (2 x 500 mL). The combined organic layers were washed with water (300 mL) and brine (100 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel; 230-400 mesh) using 2% to 4% ethyl acetate in petroleum ether as eluent to give (2S, 3S) -N, N-bis (4-methoxy Benzyl) -3-methyl-1-phenylhex-5-ene-2-sulfonamide and (2R, 3S) -N, N-bis (4-methoxybenzyl) -3-methyl-1-phenylhex-5 -En-2-sulfonamide was obtained as a colorless liquid (60.5 g, 76% yield). ¹ H NMR (400 MHz, Chloroform- d ) δ 7.28-7.14 (m, 7H), 7.02-6.92 (m, 2H), 6.90-6.84 (m, 4H), 5.60-5.52 (m, 1H), 5.04- 4.82 (m, 2H), 4.54-4.32 (m, 2H), 4.10-3.96 (m, 2H), 3.84-3.80 (m, 6H), 3.28-3.12 (m, 2H), 2.98-2.88 (m, 1H ), 2.42-2.08 (m, 1H), 2.00-1.76 (m, 2H), 1.18-1.04 (m, 3H).

Step 4: (2S, 3S) -3-methyl-1-phenylhex-5-ene-2-sulfonamide and (2R, 3S) -3-methyl-1-phenylhex-5-ene-2-sulfonamide

(2S, 3S) -N, N-bis (4-methoxybenzyl) -3-methyl-1-phenylhex-5-ene-2-sulfonamide in anisole (99 g, 915 mmol) (2R, To a stirred solution of 3S) -N, N-bis (4-methoxybenzyl) -3-methyl-1-phenylhex-5-ene-2-sulfonamide (60 g, 122 mmol) TFA (148 g, 1298) mmol) was added at 0 ° C. The resulting reaction mixture was heated to 40 ° C. for 16 hours. After the reaction is complete (monitored by TLC), the volatiles are removed under reduced pressure and subjected to flash column chromatography (silica gel; 230-400 mesh) using 15% to 20% ethyl acetate in petroleum ether as eluent. The material was purified to give (2S, 3S) -3-methyl-1-phenylhex-5-ene-2-sulfonamide and (2R, 3S) -3-methyl-1-phenylhex-5-ene-2-sulphone Amide was obtained as a liquid (21.5 g, 70% yield). MS (ESI, Anion) m / z 254.2 (M−1) ⁻ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.37-7.15 (m, 5H), 6.94-6.86 (m, 2H), 5.62-5.54 (m, 1H), 4.96-4.70 (m, 2H), 3.32 -3.20 (m, 2H), 2.92-2.80 (m, 1H), 2.49-2.28 (m, 1H), 2.10-1.78 (m, 2H), 1.08-0.90 (m, 3H).

(2S, 3S) -2,3-dimethylpent-4-ene-1-sulfonamide

Step 1: Meso-2,3-dimethylbutane-1,4-diol

A solution of meso-2,3-dimethylsuccinic acid (50.0 g, 342 mmol) in THF (700 mL) was cooled to 0 ° C. Then lithium aluminum hydride (2.0 M solution in tetrahydrofuran, 428.0 mL, 855.0 mmol) was transferred via cannula into the addition funnel and then added dropwise to the stirred cooling solution over 15 minutes. After the addition was complete, the reaction was warmed to room temperature and stirred for 12 hours under a nitrogen atmosphere. The reaction mixture was quenched by dropwise addition of MeOH (350 mL) at 0 ° C., followed by the slow addition of 20% aqueous KOH (150 mL) solution. The reaction mixture is stirred at 0 ° C. for 20 minutes, EtOAc (1000 mL) is added, the organic phase is dried over MgSO ₄ , filtered and concentrated under reduced pressure to meso-2,3-dimethylbutane-1,4- Diol was obtained (40.0 g, 100% yield) and used in these next steps. MS (ESI, cation) m / z 119.2 (M + H) ⁺ .

Step 2: rac- (2R, 3S) -4-((tert-butyldimethylsilyl) oxy) -2,3-dimethylbutan-1-ol

To a suspension of sodium hydride (60% dispersion in mineral oil, 20.31 g, 508.0 mmol) in THF (1200 mL) at 0 ° C. under N ₂ atmosphere, meso-2,3-dimethylbutane-1,4 in THF (200 mL) -Diol (40.0 g, 338.0 mmol) solution was added. After addition, the reaction was heated at 55 ° C. for 45 minutes and cooled to 0 ° C. The reaction mixture was treated with a solution of tert-butyldimethylsilyl chloride (51.0 g, 338.0 mmol) in THF (200 mL). The reaction was stirred at rt for 12 h. The reaction was quenched by addition of saturated NH ₄ Cl (500 mL) and diluted with EtOAc (500 mL). The separated aqueous layer was extracted with EtOAc (3 x 500 mL) and the combined organic extracts were washed with brine, dried over MgSO ₄ , filtered and concentrated under reduced pressure to rac- (2R, 3S) -4-((tert -Butyldimethylsilyl) oxy) -2,3-dimethylbutan-1-ol was obtained (70.0 g, 301.0 mmol, 89% yield) which was used as such in the next step. MS (ESI, cation) m / z 233.0 (M + H) ⁺ .

Step 3: rac- (2R, 3S) -4-((tert-butyldimethylsilyl) oxy) -2,3-dimethylbutanal

Rac- (2R, 3S) -4-((tert-butyldimethylsilyl) oxy) -2,3-dimethylbutan-1-ol (70.0 g, 301.0 mmol) in DCM (250 mL) and (Diace To a solution of oxyiodo) benzene (107.0 g, 301.0 mmol) 2,2,6,6-tetramethyl-1-piperidinyloxy (2.35 g, 15.06 mmol) was added at one time at room temperature. The reaction mixture was stirred at rt for 12 h. The reaction mixture was poured into DCM (500 mL) and washed with saturated aqueous sodium bicarbonate solution (250 mL) and brine (250 mL). The organic layer was dried over MgSO ₄ and concentrated under reduced pressure. Purify the crude by column chromatography using silica gel 60-120 mesh eluting with 0% to 10% EtOAc in hexane to rac- (2R, 3S) -4-((tert-butyldimethylsilyl) oxy) -2,3-dimethylbutanal was obtained (45.0 g, 195.0 mmol, 64.7% yield). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 3.51 (dd, J = 10.1, 5.2 Hz, 1H), 3.40 (dd, J = 10.0, 8.2 Hz, 1H), 2.35-2.22 (m, 2H), 0.94 (d, J = 6.8 Hz, 3H), 0.90 (d, J = 6.9 Hz, 3H), 0.83 (s, 9H). 0.03 (s, 3 H) 0.01 (s, 3 H). MS (ESI, + ve) m / z 231.2 (M + H) ⁺ .

Step 4: rac- (2S, 3S) -2,3-dimethylpent-4-en-1-ol

A solution of methyl triphenylphosphonium bromide (185.0 g, 521.0 mmol) in THF (1500 mL) was treated with n-butyllithium (2.5 M solution in hexane, 174.0 mL, 18.8 mmol) at 0 ° C. After 10 minutes, The resulting yellow mixture was stirred at room temperature for 20 minutes. A solution of rac- (2R, 3S) -4-((tert-butyldimethylsilyl) oxy) -2,3-dimethylbutanal (40.0 g, 174.0 mmol) in THF (50 mL) at -78 ° C. To the reaction mixture. After 10 minutes, the reaction mixture was stirred at 0 ° C. for 2 hours and then quenched with saturated aqueous NH ₄ Cl (500 mL) solution and water (200 mL). Diethyl ether (500 mL) was added to separate the layers. The aqueous layer was extracted with ether (3 x 500 mL). The combined organic layers were dried over MgSO ₄ and concentrated under reduced pressure to afford crude. The crude compound was dissolved in DCM (300 mL) and treated with 1.0 N HCl in diethyl ether (250 mL). The reaction mixture was stirred at rt for 30 min. The reaction mixture was concentrated under reduced pressure and the crude product was purified by column chromatography using silica gel (60-120 mesh) eluting with 0% to 30% EtOAc in hexanes to give rac- (2S, 3S) -2,3- Obtained dimethylpent-4-en-1-ol (8.0 g, 70.1 mmol, 40.2% yield). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 5.82-5.61 (m, 1H), 5.04-4.87 (m, 2H), 4.37 (t, J = 5.2 Hz, 1H), 3.39-3.25 (m, 1H ), 3.19 (ddd, J = 10.5, 6.7, 5.2 Hz, 1H), 2.33-2.16 (m, 1H), 1.56-1.36 (m, 1H), 0.95 (d, J = 6.9 Hz, 3H), 0.76 ( d, J = 6.9 Hz, 3H). MS (ESI, + ve) m / z 115.1 (M + H) ⁺ .

Step 5: rac- (2S, 3S) -2,3-dimethylpent-4-en-1-yl methanesulfonate

To a solution of rac- (2S, 3S) -2,3-dimethylpent-4-en-1-ol (5.0 g, 43.8 mmol) and triethylamine (13.43 mL, 96.0 mmol) in DCM (200 mL). Methanesulfonyl chloride (5.12 mL, 65.7 mmol, 1.5 equiv) was added at 0 ° C. The reaction mixture was stirred at 0 ° C for 1 h. The reaction is then quenched with saturated NH ₄ Cl (100 mL) solution and extracted with EtOAc (3 × 200 mL), the combined organic extracts are washed with brine, dried over MgSO ₄ , filtered and concentrated under reduced pressure. To give rac- (2S, 3S) -2,3-dimethylpent-4-en-1-yl methanesulfonate, which was used without further purification. MS (ESI, + ve) m / z 193.2 (M + H) ⁺ .

Step 6: rac-2-(((2S, 3S) -2,3-dimethylpent-4-en-1-yl) thio) pyrimidine

A solution of 2-mercapto-pyridine (27.5 g, 245.0 mmol) and potassium carbonate (36.3 g, 263.0 mmol) in DMF (1000 mL) was stirred at room temperature for 10 minutes. A solution of rac- (2S, 3S) -2,3-dimethylpent-4-en-1-yl methanesulfonate (337 g, 175.0 mmol) in THF (1000 mL) was added at room temperature. The resulting mixture was heated to 50 ° C. for 4 hours. The crude mixture was quenched with cold water (500 mL) and extracted with EtOAc (3 × 500 mL). The combined organic layers were concentrated under reduced pressure. The crude was purified by column chromatography (EtOAc / hexanes, 0% to 15%, silica gel) to rac-2-(((2S, 3S) -2,3-dimethylpent-4-en-1-yl ) Thio) pyrimidine was obtained (19.0 g, 91.0 mmol, 52% yield). ¹ H NMR (300 MHz, Chloroform-d) δ 8.50 (d, J = 4.7 Hz, 2H), 6.94 (t, J = 4.8 Hz, 1H), 5.76 (ddd, J = 16.8, 10.6, 8.2 Hz, 1H ), 5.19-4.97 (m, 2H), 3.25 (dd, J = 13.2, 5.9 Hz, 1H), 2.99 (dd, J = 13.1, 7.9 Hz, 1H), 2.50-2.32 (m, 1H), 1.93- 1.74 (m, 1 H), 1.07 (d, J = 6.8 Hz, 3H), 1.00 (d, J = 6.9 Hz, 3H). MS (ESI, + ve) m / z 209.0 (M + H) ⁺ .

Step 7: rac-2-(((2S, 3S) -2,3-dimethylpent-4-en-1-yl) sulfonyl) pyrimidine

Rac-2-(((2S, 3S) -2,3-dimethylpent-4-en-1-yl) thio) pyrimidine (25.0 g, 120.0 in acetonitrile (500 mL) and water (50 mL) mmol) was added tungsten sodium dihydrate (7.92 g, 24.0 mmol) followed by hydrogen peroxide (61.3 mL, 600.0 mmol) at 0 ° C. The reaction mixture was stirred at rt for 16 h. The reaction mixture was quenched with saturated sodium thiosulfate (750 mL). The reaction mixture was extracted with ethyl acetate (3 x 1000 mL), the combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to give rac-2-(((2S, 3S) -2,3-dimethylpent- 4-en-1-yl) sulfonyl) pyrimidine was obtained (25.0 g, 104.0 mmol, 86% yield). ¹ H NMR (400 MHz, Chloroform-d) δ 8.98 (d, J = 4.8 Hz, 2H), 7.59 (t, J = 4.9 Hz, 1H), 5.78-5.59 (m, 1H), 5.14-5.01 (m , 2H), 3.58 (dd, J = 14.3, 4.0 Hz, 1H), 3.32 (dd, J = 14.3, 8.5 Hz, 1H), 2.48-2.28 (m, 2H), 1.10 (d, J = 6.8 Hz, 3H), 1.03 (d, J = 6.8 Hz, 3H). MS (ESI, + ve) m / z 241.2 (M + H) ⁺ .

Step 8: rac- (2S, 3S) -2,3-dimethylpent-4-ene-1-sulfonamide

Methock in a solution of rac-2-(((2S, 3S) -2,3-dimethylpent-4-en-1-yl) sulfonyl) pyrimidine (25.0 g, 104.0 mmol) in methanol (500 mL) Sodium seed (22.48 g, 104.0 mmol) was added. The reaction mixture was stirred at rt for 2 h. The reaction mixture was concentrated under reduced pressure. The crude mixture was diluted with water (500 mL) and washed with ethyl acetate (3 x 250 mL). Sodium acetate (10.24 g, 125 mmol) and hydroxylamine-o-sulfonic acid (14.12 g, 125 mmol) were added to the aqueous layer. The reaction mixture was stirred at rt for 12 h. The reaction mixture was extracted with MTBE (3 x 500 mL) and the combined organic layers were washed with saturated sodium carbonate (2 x 300 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to rac- (2S, 3S)- 2,3-dimethylpent-4-ene-1-sulfonamide was obtained (14.0 g, 79.0 mmol, 76% yield). ¹ H NMR (400 MHz, Chloroform-d) δ 5.71 (ddd, J = 17.8, 10.5, 7.2 Hz, 1H), 5.19-4.92 (m, 4H), 3.19 (dd, J = 14.6, 3.7 Hz, 1H) , 2.89 (dd, J = 14.6, 8.3 Hz, 1H), 2.36 (q, J = 6.2 Hz, 1H), 2.19 (th, J = 7.5, 4.0, 3.3 Hz, 1H), 1.11 (dd, J = 6.6 , 2.9 Hz, 3H), 1.03 (dd, J = 6.7, 2.9 Hz, 3H). MS (ESI, + ve) m / z 178.2 (M + H) ⁺ .

(S) -hexahydropyrazino [2,1-c] [1,4] oxazin-4 (3H) -one

Step 1: (S) -tert-butyl 4-benzyl-2- (hydroxymethyl) piperazine-1-carboxylate

To a solution of (S) -1-boc-2- (hydroxymethyl) piperazine (5.0 g, 23.12 mmol) in 1,2-dichloroethane (100 mL) was added benzaldehyde (7.04 mL, 69.4 mmol). . The resulting mixture was then stirred for 30 minutes at room temperature and then sodium triacetoxyborohydride (6.85 mL, 46.2 mmol) was added. The resulting mixture was then stirred at rt overnight. The mixture was then quenched with saturated NaHCO ₃ (20 mL) and stirred at room temperature for 10 minutes. The organic layer was collected and the aqueous layer was extracted with EtOAc (1 x 30 mL). The combined organic layers were then dried over MgSO ₄ and concentrated in vacuo. The residue was purified by chromatography (silica gel, 0% to 100% EtOAc in heptanes) to afford (S) -tert-butyl 4-benzyl-2- (hydroxymethyl) piperazine-1-carboxylate as an oil. (5.86 g, 19.13 mmol, 83% yield). MS (ESI, cation) m / z 307.3 (M + H) ⁺ .

Step 2: (S)-(4-benzylpiperazin-2-yl) methanol

Trifluoroacetic acid (11.37 mL, 153) in a solution of (S) -tert-butyl 4-benzyl-2- (hydroxymethyl) piperazin-1-carboxylate (5.86 g, 19.13 mmol) in DCM (30 mL). mmol) was added. After addition, the mixture was stirred at rt for 2.5 h. Then further trifluoroacetic acid (7 mL) was added and the mixture was further stirred at rt for 1 h. Then the mixture was concentrated in vacuo and H ₂ O (10 mL) was added. Then the mixture was adjusted to pH = 14 with NaOH (IN). The mixture was then extracted three times with EtOAc (30 mL). The combined organic extracts were dried over MgSO ₄ , concentrated and dried overnight in vacuo at 40 ° C. to afford (S)-(4-benzylpiperazin-2-yl) methanol as an oil which was used without further purification. ¹ H NMR (400 MHz, Chloroform- d ) δ 7.26-7.38 (5H, m) 3.62-3.81 (2H, m) 3.54 (2H, d, J = 4.11 Hz) 3.25-3.35 (2H, m) 3.02-3.14 (1H, m) 2.77-2.90 (2H, m) 2.41 (1H, td, J = 11.88, 2.45 Hz) 2.18-2.30 (1H, m). MS (ESI, cation) m / z 207.1 (M + H) ⁺ .

Step 3: (S) -1- (4-benzyl-2- (hydroxymethyl) piperazin-1-yl) -2-chloroethanone

Chlorochloride in a 0 ° C. solution of (S)-(4-benzylpiperazin-2-yl) methanol (1.4 g, 6.79 mmol) and triethylamine (2.83 mL, 20.36 mmol) in DCM (5 mL) under N ₂ Acetyl (0.540 mL, 6.79 mmol) was added dropwise. After addition, the mixture was stirred at 0 ° C. for 48 minutes. Then MeOH (10 mL) was added and the mixture was concentrated in vacuo. The residue was purified by chromatography (silica gel, 0% to 100% EtOAc in heptanes) to give (S) -1- (4-benzyl-2- (hydroxymethyl) piperazin-1-yl) -2-chloro Ethanone was obtained as an oil (530 mg, 1.874 mmol, 27.6% yield). MS (ESI, cation) m / z 283.1 (M + H) ⁺ .

Step 4: (S) -8-benzylhexahydropyrazino [2,1-c] [1,4] oxazin-4 (3H) -one

0 ° C. of (S) -1- (4-benzyl-2- (hydroxymethyl) piperazin-1-yl) -2-chloroethanone (530 mg, 1.874 mmol) in THF (40 mL) under N ₂ To the solution was added potassium tert-butoxide (421 mg, 3.75 mmol). After addition, the mixture was stirred at 0 ° C. for 2 hours. LCMS did not show starting material. Then MeOH (10 mL) was added and the mixture was concentrated in vacuo. The residue was purified by chromatography (silica gel, 0% to 100% EtOAc in heptanes) to give (S) -8-benzylhexahydropyrazino [2,1-c] [1,4] oxazine-4 (3H ) -One was obtained as an oil (262 mg, 1.064 mmol, 56.8% yield). MS (ESI, cation) m / z 247.1 (M + H) ⁺ .

Step 4: (S) -hexahydropyrazino [2,1-c] [1,4] oxazin-4 (3H) -one

(S) -8-benzylhexahydropyrazino [2,1-c] [1,4] oxazin-4 (3H) -one (262 mg, 1.064 mmol) in methanol (2.5 mL) in a pressure vial; To a solution of acetic acid (0.123 mL, 2.127 mmol) was added palladium (5% in activated carbon, 34 mg, 0.319 mmol) in EtOAc (0.3 mL). The mixture was then degassed five times with hydrogen and then charged with hydrogen at 40 psi. Then the mixture was stirred for 3.5 hours. LCMS showed some starting material. Then palladium (5% in activated carbon, 34 mg, 0.319 mmol) and acetic acid (0.123 mL, 2.127 mmol) were added. The mixture was then degassed five times with hydrogen and then charged with hydrogen at 40 psi. The resulting mixture was stirred overnight at 40 psi at room temperature. The mixture was then filtered through celite and the celite was washed with MeOH / EtOAc 1: 1 (2 × 3 mL). The combined filtrates were concentrated and dried in vacuo to afford (S) -hexahydropyrazino [2,1-c] [1,4] oxazin-4 (3H) -one as an oil (166 mg, 1.063 mmol). , 100% yield), which was used without further purification. MS (ESI, cation) m / z 157.1 (M + H) ⁺ .

(3S, 9aS) -3-methylhexahydropyrazino [2,1-c] [1,4] oxazin-4 (3H) -one and (3R, 9aS) -3-methylhexahydropyrazino [2 , 1-c] [1,4] oxazine-4 (3H) -one

Step 1: (S) -1-((S) -4-benzyl-2- (hydroxymethyl) piperazin-1-yl) -2-chloropropan-1-one and (R) -1-(( S) -4-benzyl-2- (hydroxymethyl) piperazin-1-yl) -2-chloropropan-1-one

2-chlorochloropropylate in a 0 ° C. solution of (S)-(4-benzylpiperazin-2-yl) methanol (1.4 g, 6.79 mmol) and triethylamine (2.83 mL, 20.36 mmol) in DCM (10 mL). O'Neill (0.862 mL, 6.79 mmol) was added. After addition, the mixture was stirred at 0 ° C. for 2 hours. LCMS did not show starting material. Then MeOH (10 mL) was added and the mixture was concentrated in vacuo. The residue was purified by chromatography (silica gel, 0% to 100% EtOAc in heptanes) to (S) -1-((S) -4-benzyl-2- (hydroxymethyl) piperazin-1-yl) 2-Chloropropan-1-one was obtained as an oil and as an isomer first eluting on a silica gel column (176 mg, 0.593 mmol, 8.74% yield). ¹ H NMR (400 MHz, Chloroform- d ) δ 7.28-7.40 (5H, m) 4.46-4.73 (2H, m) 4.14 (1H, br s) 3.69-4.03 (3H, m) 3.41-3.63 (2H, m A) 3.10 (1 H, br s) 2.93 (1 H, br s) 2.35 (1 H, br s) 2.02-2.23 (1 H, m) 1.65-1.69 (3 H, m). MS (ESI, cation) m / z 297.0 (M + H) ⁺ . Additionally, (R) -1-((S) -4-benzyl-2- (hydroxymethyl) piperazin-1-yl) -2-chloropropan-1-one as oil and a second in a silica gel column Isolated as eluting isomer (142 mg, 0.478 mmol, 7.1% yield). ¹ H NMR (400 MHz, Chloroform- d ) δ 7.27-7.40 (5H, m), 4.60-4.72 (1H, m), 4.44-4.59 (1H, m), 3.97 (1H, d, J = 4.30 Hz) , 3.68-3.93 (3H, m), 3.51 (2H, d, J = 18.58 Hz), 3.07 (1H, br s), 2.92 (1 H, br s), 2.11-2.45 (2H, m), 1.64- 1.73 (3 H, m). MS (ESI, cation) m / z 297.0 (M + H) ⁺ .

Step 2: (3S, 9aS) -8-benzyl-3-methylhexahydropyrazino [2,1-c] [1,4] oxazin-4 (3H) -one

(R) -1-((S) -4-benzyl-2- (hydroxymethyl) piperazin-1-yl) -2-chloropropan-1-one (142 mg, in THF (50 mL) under nitrogen) 0.478 mmol) was added potassium tert-butoxide (59.1 mg, 0.526 mmol). The resulting mixture was then stirred at 0 ° C. for 1 hour and at room temperature for 10 days. Then MeOH (10 mL) was added and the mixture was concentrated in vacuo. The residue was purified by chromatography (silica gel, 0% to 100% EtOAc in heptanes) to (3S, 9aS) -8-benzyl-3-methylhexahydropyrazino [2,1-c] [1,4] Oxazine-4 (3H) -one was obtained as an oil (33 mg, 0.127 mmol, 26.5% yield). ¹ H NMR (400 MHz, Dichloromethane-d2) δ 7.11-7.28 (6H, m), 4.31-4.42 (1H, m), 4.02-4.10 (1H, m), 3.69-3.77 (1H, m), 3.54-3.63 (1H, m), 3.37-3.49 (3H, m), 2.63-2.80 (3H, m), 1.92-2.05 (2H, m), 1.31 (3H, d, J = 6.85 Hz). MS (ESI, cation) m / z 261.1 (M + H) ⁺ .

Step 3: (3S, 9aS) -3-methylhexahydropyrazino [2,1-c] [1,4] oxazin-4 (3H) -one

(3S, 9aS) -8-benzyl-3-methylhexahydropyrazino [2,1-c] [1,4] oxazin-4 (3H) -one (33 mg, 0.127 mmol) in methanol (0.5 mL) ) Was added acetic acid (0.015 mL, 0.254 mmol) and palladium (10 wt% wet degussa type on dry basis in activated carbon), 6.74 mg, 0.063 mmol). The resulting mixture was then purged with hydrogen and then filled with hydrogen at 40 psi. The resulting mixture was then stirred at rt overnight. Then the mixture was filtered through celite and the celide was washed with EtOAc (2 x 3 mL). The combined filtrates were concentrated in vacuo and the residue was purified by chromatography (silica gel, 0% to 50% MeOH in DCM) to give (3S, 9aS) -3-methylhexahydropyrazino [2,1-c] [ 1,4] oxazin-4 (3H) -one was obtained as an oil (20 mg, 0.118 mmol, 93% yield). ¹ H NMR (400 MHz, Dichloromethane-d2) δ 4.43-4.58 (1H, m), 4.09-4.19 (1H, m), 3.86 (1H, dd, J = 12.52, 4.50 Hz), 3.66-3.75 ( 1H, m), 3.53 (1H, td, J = 7.53, 3.72 Hz), 2.97-3.12 (2H, m), 2.65-2.87 (3H, m), 1.41 (3H, d, J = 6.85 Hz). MS (ESI, cation) m / z 171.1 (M + H) ⁺ .

Step 4: (3R, 9aS) -8-benzyl-3-methylhexahydropyrazino [2,1-c] [1,4] oxazin-4 (3H) -one

(S) -1-((S) -4-benzyl-2- (hydroxymethyl) piperazin-1-yl) -2-chloropropan-1-one (176 mg, in THF (50 mL) under nitrogen) 0.593 mmol) in THF (50 mL) was added potassium tert-butoxide (100 mg, 0.890 mmol). After addition, the mixture was stirred at 0 ° C. for 30 minutes. LCMS did not show starting material. Then saturated NaHCO ₃ (5 mL) was added and the mixture was extracted twice with EtOAc (20 mL). The combined organic extracts were dried over MgSO ₄ , concentrated and dried in vacuo (3R, 9aS) -8-benzyl-3-methylhexahydropyrazino [2,1-c] [1,4] oxazine-4 (3H) -one was obtained as an oil (154 mg, 0.592 mmol, 100% yield) which was used without purification. MS (ESI, cation) m / z 261.0 (M + H) ⁺ .

Step 5: (3R, 9aS) -3-methylhexahydropyrazino [2,1-c] [1,4] oxazin-4 (3H) -one

(3R, 9aS) -8-benzyl-3-methylhexahydropyrazino [2,1-c] [1,4] oxazin-4 (3H) -one (154 mg, 0.592 mmol) in methanol (2 mL) To a solution of) was added a solution of palladium (10 wt% of wet degussa type, 18.89 mg, 0.177 mmol) on a dry basis in activated carbon in EtOAc (0.2 mL). The resulting mixture was then purged five times with hydrogen and filled with hydrogen at 40 psi. The resulting mixture was then stirred for 10 days. Then the mixture was filtered through celite and the clide was washed with EtOAc (2 x 5 mL). The combined filtrates were concentrated. The residue was purified by chromatography (silica gel, 0% to 20% MeOH in DCM) to give (3R, 9aS) -3-methylhexahydropyrazino [2,1-c] [1,4 ] Oxazin-4 (3H) -one was obtained as an oil (93 mg, 0.546 mmol, 92% yield). ¹ H NMR (400 MHz, Dichloromethane-d2) δ ppm 4.27-4.45 (1H, m), 4.05 (1H, q, J = 6.85 Hz), 3.74 (1H, dd, J = 12.23, 4.60 Hz), 3.54-3.63 (1H, m), 3.24-3.36 (1H, m), 2.84-2.91 (1H, m), 2.80 (1H, dd, J = 11.74, 2.74 Hz), 2.50-2.67 (3H, m), 1.32 (3H, doublet, J = 6.85 Hz). MS (ESI, cation) m / z 171.1 (M + H) ⁺ .

(3S, 9aS) -3-methyloctahydropyrazino [2,1-c] [1,4] oxazine

(3S, 9aS) -3-methylhexahydropyrazino [2,1-c] [1,4] oxazin-4 (3H) -one (52 mg) in 1,4-dioxane (4 mL) under nitrogen , 0.306 mmol) was added dropwise to lithium aluminum hydride (2.0 M in THF, 1.22 mL, 2.44 mmol). After addition, the mixture was stirred at 80 ° C. for 6 hours. The mixture was then quenched with 2-propanol (1 mL) at 0 ° C. followed by saturated Na ₂ SO _{4 (} 3 mL). The mixture was then stirred at room temperature for 39 minutes and then filtered. The filtered cake was washed with MeOH (2 x 5 mL). The combined filtrates were concentrated and dried in vacuo. Then the residue was dissolved in MeOH (5 mL) and silica gel was added. The mixture was concentrated and dried in vacuo. The solid mixture was then purified by silica gel chromatography using an ISCO instrument (solid addition, 0% to 20% ammonia dissolved in 2M MeOH in DCM) to give (3S, 9aS) -3-methyloctahydropyrazino. [2,1-c] [1,4] oxazine was obtained as a solid containing residual solvent (67 mg, 0.429 mmol, 140% yield) which was used without further purification. ¹ H NMR (400 MHz, Chloroform- d ) δ 3.94 (1H, dt, J = 6.55, 3.37 Hz), 3.72 (1H, q, J = 7.04 Hz), 3.52-3.59 (2H, m), 3.03-3.10 (2H, m), 2.86-2.96 (1H, m), 2.68-2.82 (5H, m), 1.90 (1H, br s), 1.34 (3H, d, J = 6.65 Hz). MS (ESI, cation) m / z 157.1 (M + H) ⁺ .

(3R, 9aS) -3-methyloctahydropyrazino [2,1-c] [1,4] oxazine

(3R, 9aS) -3-methylhexahydropyrazino [2,1-c] [1,4] oxazin-4 (3H) -one (80 mg in 1,4-dioxane (5 mL) under N2 To a room temperature solution of 0.470 mmol), lithium aluminum hydride (1.0 M in THF, 1.88 mL, 1.88 mmol) was added dropwise. After addition, the mixture was stirred at 80 ° C. for 6 hours. The mixture was then quenched with 2-propanol (1 mL) at 0 ° C. followed by saturated Na ₂ SO ₄ (3 mL). The mixture was then stirred at room temperature for 39 minutes and then filtered. The filtered cake was washed with MeOH (2 x 5 mL). The combined filtrates were concentrated and dried in vacuo. Then the residue was dissolved in MeOH (5 mL) and silica gel was added. The mixture was concentrated and dried in vacuo. The solid mixture was then purified by silica gel column chromatography using an ISCO instrument (solid addition, 0% to 20% ammonia dissolved in 2M MeOH in DCM) to give (3R, 9aS) -3-methyloctahydropyra. Gino [2,1-c] [1,4] oxazine was obtained as an oil (20 mg, 0.128 mmol, 27.2% yield). ¹ H NMR (400 MHz, Dichloromethane-d2) δ 3.92 (1H, ddd, J = 6.50, 3.96, 2.25 Hz), 3.42-3.50 (1H, m), 3.30-3.37 (1H, m), 2.79- 2.92 (2H, m), 2.53-2.68 (2H, m), 2.37-2.50 (3H, m), 2.06-2.24 (2H, m), 1.90 (1H, br s), 1.33 (3H, d, J = 6.65 Hz). MS (ESI, cation) m / z 157.2 (M + H) ⁺ .

(R) -hexahydro-1H-pyrido [1,2-a] pyrazine-4 (6H) -one

Step 1: (R) -tert-butyl 2-((((benzyloxy) carbonyl) amino) methyl) piperidine-1-carboxylate

I Pr ₂ Net (0.424 mL, 2.438 mmol) in a 0 ° C. solution of (R) -tert-butyl 2- (aminomethyl) piperidine-1-carboxylate (475 mg, 2.216 mmol) in DCM (5.0 mL) Was added followed by benzyl chloroformate (0.693 mL, 2.438 mmol). The resulting mixture was then stirred at 0 ° C. for 2 hours and at room temperature for 14 hours. Saturated NaHCO _{3 (} 30 mL) was then added to the mixture and stirred for 3 minutes at room temperature. The organic layer was collected and the aqueous layer was extracted with EtOAc (1 x 20 mL). The combined organic extracts were dried over Na ₂ S0 ₄ and concentrated in vacuo. The residue was purified by chromatography (silica gel, 0% to 100% EtOAc in heptanes) to give (R) -tert-butyl 2-(((((benzyloxy) carbonyl) amino) methyl) piperidine-1 -Carboxylate was obtained as an oil (772 mg, 2.216 mmol, 100% yield). MS (ESI, cation) m / z 371.1 (M + Na) ⁺ .

Step 2: (R) -benzyl (piperidin-2-ylmethyl) carbamate

Trifluoro in a solution of (R) -tert-butyl 2-((((benzyloxy) carbonyl) amino) methyl) piperidine-1-carboxylate (772 mg, 2.216 mmol) in DCM (5 mL) Acetic acid (1.646 mL, 22.16 mmol) was added. The resulting mixture was then stirred for 2 hours at room temperature. Then, i Pr ₂ Net (3.85 mL, 22.16 mmol) was added dropwise to the mixture at 0 ° C. and stirred at room temperature for 5 minutes. The mixture is then concentrated in vacuo and the residue is purified by chromatography (silica gel, 3: 1 ratio of EtOH: EtOAc (0% to 100%) in heptane) to (R) -benzyl (piperidine- 2-ylmethyl) carbamate was obtained as an oil (495 mg, 90% yield). MS (ESI, cation) m / z 249.2 (M + H) ⁺ .

Step 3: (R) -benzyl ((1- (2-chloroacetyl) piperidin-2-yl) methyl) carbamate

To a 0 ° C. solution of (R) -benzyl (piperidin-2-ylmethyl) carbamate (150 mg, 0.604 mmol) in DCM (1 mL) under nitrogen followed by i Pr ₂ Net (0.168 mL, 0.966 mmol) Chloroacetyl chloride (0.063 mL, 0.785 mmol) was added. After addition, the mixture was stirred at 0 ° C. for 1 hour. The mixture was then quenched with saturated NaHCO ₃ (2.5 mL) and extracted with EtOAc (2 × 3 mL). The combined organic extracts were then dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by chromatography (silica gel, 0% to 100% EtOAc in heptanes) to afford (R) -benzyl ((1- (2-chloroacetyl) piperidin-2-yl) methyl) carbamate solid Obtained as (126 mg, 0.388 mmol, 64.2% yield). MS (ESI, cation) m / z 325.1 (M + H) ⁺ .

Step 4: (R) -Benzyl 4-oxohexahydro-1H-pyrido [1,2-a] pyrazine-2 (6H) -carboxylate

Sodium hydride (in mineral oil) in a solution of (R) -benzyl ((1- (2-chloroacetyl) piperidin-2-yl) methyl) carbamate (126 mg, 0.388 mmol) in tetrahydrofuran (5 mL) 60% dispersion, 31 mg, 0.776 mmol) was added several times. After addition, the mixture was stirred at rt for 5 h. The mixture was then quenched carefully with water (5 mL). The mixture was then extracted twice with EtOAc (10 mL). The combined organic extracts were then dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by chromatography (silica gel, 0% to 100% EtOAc in heptanes) to give (R) -benzyl 4-oxohexahydro-1H-pyrido [1,2-a] pyrazine-2 (6H)- Carboxylate was obtained as an oil (112 mg, 0.388 mmol, 100% yield). MS (ESI, cation) m / z 289.1 (M + H) ⁺ .

Step 5: (R) -hexahydro-1H-pyrido [1,2-a] pyrazine-4 (6H) -one

To a solution of (R) -benzyl 4-oxohexahydro-1H-pyrido [1,2-a] pyrazine-2 (6H) -carboxylate (112 mg, 0.388 mmol) in ethanol (3 mL) was added ammonium formate ( 122 mg, 1.942 mmol) and 10% palladium in carbon (124 mg, 0.117 mmol) were added. The resulting mixture was then stirred at 70 ° C. for 1 hour. The mixture was filtered through celite and the filter cake was washed three times with a 1: 1 mixture of EtOAc and MeOH (2 mL). The combined filtrates were concentrated and the residue was purified by chromatography (silica gel, 2 M ammonia (0% to 15%) dissolved in MeOH in DCM) to give (R) -hexahydro-1H-pyrido [1,2 -a] pyrazin-4 (6H) -one was obtained as an oil (54 mg, 0.350 mmol, 90% yield). MS (ESI, cation) m / z 155.1 (M + H) ⁺ _.

1- (dihydro-1H-pyrazino [1,2-a] pyrazine-2 (6H, 7H, 8H, 9H, 9aH) -yl) ethanone

Step 1: tert-butyl 8-acetylhexahydro-1H-pyrazino [1,2-a] pyrazine-2 (6H) -carboxylate

Diisopropylethyl in a room temperature stirred solution of tert-butyl hexahydro-1H-pyrazino [1,2-a] pyrazine-2 (6H) -carboxylate (0.680 g, 2.82 mmol) in DCM (10 mL) under argon. Amine (1.078 mL, 6.20 mmol) was added followed by 2,5-dioxopyrrolidin-1-yl acetate (0.885 g, 5.64 mmol) at a time as a solid. The resulting mixture was stirred at rt for 24 h. The crude mixture was added directly to a silica gel precolumn (25 g) pre-topped with a sodium bicarbonate layer and purified by flash column chromatography using an ISCO gold column eluting with 0% to 3% MeOH in DCM to give tert-butyl 8- Acetylhexahydro-1H-pyrazino [1,2-a] pyrazine-2 (6H) -carboxylate was obtained as an oil. It was used for the next step without further purification. MS (ESI, cation) m / z 306.4 (M + Na) ⁺ .

Step 2: 1- (dihydro-1H-pyrazino [1,2-a] pyrazine-2 (6H, 7H, 8H, 9H, 9aH) -yl) ethanone

To a solution of tert-butyl 8-acetylhexahydro-1H-pyrazino [1,2-a] pyrazine-2 (6H) -carboxylate (10 mL) in DCM (10 mL) 2,2,2-trifluoro Roacetic acid (2.0 mL) was added at room temperature. The resulting mixture was stirred overnight at room temperature and volatiles were removed to remove 1- (hexahydro-1H-pyrazino [1,2-a] pyrazin-2 (6H) -yl) ethanone 2,2,2-trifluoro Loacetate was obtained as a solid and used without further purification.

2- (methylsulfonyl) octahydro-1H-pyrazino [1,2-a] pyrazine

Step 1: tert-butyl 8- (methylsulfonyl) hexahydro-1H-pyrazino [1,2-a] pyrazine-2 (6H) -carboxylate

Tert-butyl hexahydro-1H-pyrazino [1,2-a] pyrazine-2 (6H) -carboxylate (1.000 g, 4.14 mmol) and diisopropylethylamine (1.442 mL, 8.29) in DCM (14 mL) mmol) and methanesulfonyl chloride (0.385 mL, 4.97 mmol) was added dropwise through a syringe to the ice-cooled mixture. The resulting mixture was stirred at 0 ° C. for 10 minutes and at ambient temperature for 19 hours. Remove volatiles, add residue to silica gel precolumn (25 g) and purify by combi-flash column chromatography using ISCO gold column eluting with 0% to 100% MeOH in DCM to tert-butyl 8- (methylsulfonyl) hexahydro-1H-pyrazino [1,2-a] pyrazine-2 (6H) -carboxylate was obtained as an oil (1.30 g, 4.07 mmol, 98% yield). MS (ESI, cation) m / z 320.1 (M + l) ⁺ .

Step 2: 2- (methylsulfonyl) octahydro-1H-pyrazino [1,2-a] pyrazine

To a stirred solution of tert-butyl 8- (methylsulfonyl) hexahydro-1H-pyrazino [1,2-a] pyrazine-2 (6H) -carboxylate (1.30 g, 4.07 mmol) in DCM (20 mL) 2,2,2-trifluoroacetic acid (2.0 mL, 4.14 mmol) was added via syringe. The resulting mixture was stirred at rt for 2.5 h. Additional TFA (2 X 2.5 mL) was added over the first 2 hours. The volatiles were removed in vacuo and the residue was treated under high vacuum overnight to yield 2.4 g of 2- (methylsulfonyl) octahydro-1H-pyrazino [1,2-a] pyrazine 2,2,2-trifluoro Acetate was obtained as a solid, which was used without further purification. MS (ESI, cation) m / z 220.2 (M + l) ⁺ .

1- (dihydro-1H-pyrazino [1,2-a] pyrazine-2 (6H, 7H, 8H, 9H, 9aH) -yl) -3- (phenylsulfonyl) propan-1-one

Step 1: tert-butyl 8- (3- (phenylsulfonyl) propanoyl) hexahydro-1H-pyrazino [1,2-a] pyrazine-2 (6H) -carboxylate

Tert-butyl hexahydro-1H-pyrazino [1,2-a] pyrazine-2 (6H) -carboxylate (0.46 g, 1.906 mmol) and 3- (phenylsulfonyl) propionic acid (0.490) in DCM (6.5 mL) g, 2.287 mmol) to a stirred solution at room temperature was added i Pr ₂ Net (0.829 mL, 4.77 mmol) via syringe, followed by HATU (1.450 g, 3.81 mmol) in one portion as a solid. The resulting mixture was stirred at rt for 75 min. The crude mixture was added directly onto silica gel precolumn (25 g) and purified by Combi Flash column chromatography using 24 g ISCO Gold column eluting with 0% to 15% MeOH in DCM to 1.28 g tert-butyl 8 -(3- (phenylsulfonyl) propanoyl) hexahydro-1H-pyrazino [1,2-a] pyrazine-2 (6H) -carboxylate is obtained as an oil which is used in the next step without further purification. It was. MS (ESI, cation) m / z 438.2 (M + l) ⁺ .

Step 2: 1- (dihydro-1H-pyrazino [1,2-a] pyrazine-2 (6H, 7H, 8H, 9H, 9aH) -yl) -3- (phenylsulfonyl) propan-1-one

Tert-butyl 8- (3- (phenylsulfonyl) propanoyl) hexahydro-1H-pyrazino [1,2-a] pyrazine-2 (6H) -carboxylate (1.28 g, in DCM) 2.93 mmol) and 2,2,2-trifluoroacetic acid (4.0 mL, 2.93 mmol) were stirred at room temperature for 50 minutes. 1.5 g of 1- (dihydro-1H-pyrazino [1,2-a] pyrazine-2 (6H, 7H, 8H, 9H, 9aH) -yl by removing the volatiles and treating the residue with high vacuum overnight ) -3- (phenylsulfonyl) propan-1-one as an oil, which was used without further purification. MS (ESI, cation) m / z 338.1 (M + l) ⁺ .

2-isopropyloctahydro-1H-pyrazino [1,2-a] pyrazine

Step 1: tert-butyl 8-isopropylhexahydro-1H-pyrazino [1,2-a] pyrazine-2 (6H) -carboxylate

Tert-butyl hexahydro-1H-pyrazino [1,2-a] pyrazine-2 (6H) -carboxylate (0.53 g, 2.196 mmol) and acetone (0.806 mL, 10.98 mmol) in DCM (5.0 mL) After stirring for 10 minutes at room temperature, sodium triacetoxyhydroborate (2.327 g, 10.98 mmol) was added in one portion at room temperature as a solid. The resulting mixture was stirred at rt for 24 h. The reaction was quenched with MeOH (5 mL), the resulting slurry was added directly to silica gel precolumn (25 g), and the combi- using 12 g ISCO gold column eluting with 0% to 20% MeOH in DCM. Purification by flash chromatography gave tert-butyl 8-isopropylhexahydro-1H-pyrazino [1,2-a] pyrazine-2 (6H) -carboxylate (0.65 g, 2.293 mmol, 104% yield) as an oil. Obtained. MS (ESI, cation) m / z 284.3 (M + l) ⁺ .

Step 2: 2-isopropyloctahydro-1H-pyrazino [1,2-a] pyrazine

Tert-butyl 8-isopropylhexahydro-1H-pyrazino [1,2-a] pyrazine-2 (6H) -carboxylate (0.65 g, 2.293 mmol) and 2,2,2- in DCM (15 mL) A mixture of trifluoroacetic acid (4.0 mL, 2.293 mmol) was stirred at rt for 2 h. The volatiles were removed in vacuo and the residue was treated under high vacuum overnight to yield 1.74 g of 2-isopropyloctahydro-1H-pyrazino [1,2-a] pyrazine as an oil which was used without further purification. . MS (ESI, cation) m / z 184.2 (M + l) ⁺ .

(1R, 4R) -2-isopropyl-2,5-diazabicyclo [2.2.1] heptane

(1R, 4R) -tert-butyl 2,5-diazabicyclo [2.2.1] heptane using the same protocol for synthesizing 2-isopropyloctahydro-1H-pyrazino [1,2-a] pyrazine The title compound was synthesized from -2-carboxylate (AstaTech, Inc.). MS (ESI, cation) m / z 141.2 (M + l) ⁺ .

(1S, 4S) -2-isopropyl-2,5-diazabicyclo [2.2.1] heptane

(1S, 4S) -tert-butyl 2,5-diazabicyclo [2.2.1] heptane using the same protocol for synthesizing 2-isopropyloctahydro-1H-pyrazino [1,2-a] pyrazine The title compound was synthesized from -2-carboxylate (AstaTech, Inc.). MS (ESI, cation) m / z 141.2 (M + l) ⁺ .

Cis-1- (2-methoxyethyl) -2,6-dimethylpiperazine

From cis-tert-butyl 3,5-dimethylpiperazine-1-carboxylate (AK Scientific) using a protocol for synthesizing 2-isopropyloctahydro-1H-pyrazino [1,2-a] pyrazine as well The title compound was synthesized. MS (ESI, cation) m / z 173.2 (M + l) ⁺ .

Cis-1-isopropyl-2,6-dimethylpiperazine and cis-2,6-dimethylpiperazine

From cis-tert-butyl 3,5-dimethylpiperazine-1-carboxylate (AK Scientific) using a protocol for synthesizing 2-isopropyloctahydro-1H-pyrazino [1,2-a] pyrazine as well The title compound was synthesized and used as a mixture. MS (ESI, cation) m / z 157.1 and 115.3 (M + 1) ⁺ .

(S) -1-Isopropyl-2-methylpiperazine

The title compound was synthesized from (S) -tert-butyl 3-methylpiperazin-1-carboxylate using the same protocol for synthesizing 2-isopropyloctahydro-1H-pyrazino [1,2-a] pyrazine. . MS (ESI, cation) m / z 143.2 (M + l) ⁺ .

1- (1,4-dioxepan-6-yl) piperazine

The title compound was synthesized from 1,4-dioxepan-6-one (Enamine) using the same protocol to synthesize 2-isopropyloctahydro-1H-pyrazino [1,2-a] pyrazine. MS (ESI, cation) m / z 187.2 (M + l) ⁺ .

(2S, 6S) -1-isopropyl-2,6-dimethylpiperazine

Using the same protocol for synthesizing 2-isopropyloctahydro-1H-pyrazino [1,2-a] pyrazine, (3S, 5S) -tert-butyl 3,5-dimethylpiperazine-1-carboxylate ( Anichem) synthesized the title compound. MS (ESI, cation) m / z 157.2 (M + l) ⁺ .

4- (2-methoxyethyl) piperazin-2-one

The title compound was synthesized from piperazin-2-one (AK Scientific) using a protocol for synthesizing 2-isopropyloctahydro-1H-pyrazino [1,2-a] pyrazine (step 1) as well.

1- (oxetan-3-ylmethyl) piperazine

The title compound was synthesized from tert-butyl piperazine-1-carboxylate using a protocol for synthesizing 2-isopropyloctahydro-1H-pyrazino [1,2-a] pyrazine as well. MS (ESI, cation) m / z 157.1 (M + l) ⁺ .

4- (piperazin-1-yl) tetrahydro-2H-pyran-2-one

To a stirred solution of 5,6-dihydro-2h-pyran-2-one (0.228 mL, 2.65 mmol) in DCM (1.0 mL) piperazine-1-carboxylic acid tert-butyl ester (469 mg) in DCM (2.0 mL) , 2.52 mmol) was added under argon. The resulting mixture was stirred at room temperature for a period of 3 days, after which trifluoroacetic acid (2.5 mL, 33.7 mmol) was added dropwise via syringe. The resulting mixture was stirred at rt for 2 h. The mixture was concentrated in vacuo and the residue was dried to afford 4- (piperazin-1-yl) tetrahydro-2H-pyran-2-one with impurities. It was used without further purification. MS (ESI, cation) m / z 185.1 (M + l) ⁺ .

8,8-difluorooctahydro-1H-pyrido [1,2-a] pyrazine and 8-fluorooctahydro-1H-pyrido [1,2-a] pyrazine

Step 1: 2-benzyl-8,8-difluorooctahydro-1H-pyrido [1,2-a] pyrazine and 2-benzyl-8-fluoro-2,3,4,6,7,9a -Hexahydro-1H-pyrido [1,2-a] pyrazine and 2-benzyl-8-fluoro-2,3,4,6,9,9a-hexahydro-1H-pyrido [1,2- a] pyrazine

Stirred solution of 2-benzylhexahydro-1H-pyrido [1,2-a] pyrazine-8 (2H) -one (200 mg, 0.819 mmol, AstaTech) in DCM (5.0 mL) cooled in brine-ice bath. Ebis (2-methoxyethyl) aminosulfur trifluoride solution (50% in THF, 0.989 mL, 2.456 mmol) was added dropwise via syringe. The resulting mixture was stirred at −5 ° C. for 2 hours and at ambient temperature for 3 hours. The crude mixture was added directly to silica gel precolumn (25 g) and purified by flash column chromatography using 12 g ISCO gold column eluting with 0% to 10% MeOH in DCM to 170 mg of 2-benzyl- 8,8-difluorooctahydro-1H-pyrido [1,2-a] pyrazine, 2-benzyl-8-fluoro-2,3,4,6,7,9a-hexahydro-1H-pyri A mixture of do [1,2-a] pyrazine and 2-benzyl-8-fluoro-2,3,4,6,9,9a-hexahydro-1H-pyrido [1,2-a] pyrazine Obtained. The mixture was used directly in the next step. MS (ESI, cation) m / z 267.2 and 247.2 (M + 1) ⁺ .

Step 2: 8,8-difluorooctahydro-1H-pyrido [1,2-a] pyrazine and 8-fluorooctahydro-1H-pyrido [1,2-a] pyrazine

2-benzyl-8,8-difluorooctahydro-1H-pyrido [1,2-a] pyrazine, 2-benzyl-8-fluoro-2,3,4,6, in EtOH (25 mL) 7,9a-hexahydro-1H-pyrido [1,2-a] pyrazine and 2-benzyl-8-fluoro-2,3,4,6,9,9a-hexahydro-1H-pyrido [1 , 2-a] A mixture of pyrazine (250 mg, 0.939 mmol) and palladium (5 wt% wet degussa type on activated carbon, activated by spatula) and concentrated hydrochloric acid (5 mL) for 22 h. Hydrogen was added with hydrogen gas at 45 psi. The reaction was quenched with water (5 mL) and the mixture was filtered through a layer of sanded celite. The filtrate was concentrated in vacuo to afford colorless 8,8-difluorooctahydro-1H-pyrido [1,2-a] pyrazine and 8-fluorooctahydro-1H-pyrido [1,2-a] pyrazine Obtained as a membrane, which was used without further purification. MS (ESI, cation) m / z 177.2 and 159.2 (M + 1) ⁺ .

1- (5- (piperazin-1-yl) -2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) ethanone

Step 1: tert-butyl 4- (3-acetyl-4-hydroxyphenyl) piperazine-1-carboxylate

5'-Bromo-2'-hydroxyacetophenone (2.000 g, 9.30 mmol, Oakwood), 1-boc-piperazine (2.77 g, 14.88 mmol) in THF (20 mL), tris (dibenzylideneacetone) Dipalladium (0) (0.426 g, 0.465 mmol), and 2- (dichlorohexylphosphino) -2 '-(n, n-dimethylamino) diphenyl (0.183 g, 0.465 mmol) were stirred for ice cooling To the mixture was added dropwise linin bis (trimethylsilyl) amide (1.0 M in THF, 32.6 mL, 32.6 mmol). The resulting mixture was stirred at ambient temperature for 10 minutes and then placed in an oil bath at room temperature. The oil bath was then heated to 70 ° C. and the reaction mixture was stirred at this temperature for 1.5 hours. The mixture was cooled in an ice bath and then carefully quenched with ice cold saturated aqueous ammonium chloride solution. The resulting mixture was poured into a mixture of 1 N HCl aqueous solution and saturated aqueous ammonium chloride solution and extracted twice with 10% MeOH / DCM. The combined organics were washed with saturated aqueous ammonium chloride solution, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was dissolved in DCM and added to silica gel precolumn and purified by flash column chromatography using 40 g ISCO gold column eluting with 0% to 4% MeOH in DCM to 1.84 g tert-butyl 4- (3-acetyl-4-hydroxyphenyl) piperazine-1-carboxylate was obtained and used directly in the next step. MS (ESI, cation) m / z 321.2 (M + l) ⁺ .

Step 2: tert-butyl 4- (3-acetyl-4- (trifluoromethylsulfonyloxy) phenyl) piperazine-1-carboxylate

Tert-butyl 4- (3-acetyl-4-hydroxyphenyl) piperazine-1-carboxylate (1.30 g, 4.06 mmol) and triethylamine (2.258 mL, 16.23 mmol) with impurities in DCM (15 mL) N-phenyl bis-trifluoromethane sulfonamide (2.90 g, 8.12 mmol) was added in one portion as a solid to the stirred solution. The resulting mixture was stirred at ambient temperature for 2.5 days. The crude mixture was added directly onto silica gel precolumn (25 g) and purified by flash column chromatography using 40 g ISCO gold column eluting with 10% to 40% EtOAc in hexanes to give tert-butyl 4- ( 3-acetyl-4-(((trifluoromethyl) sulfonyl) oxy) phenyl) piperazine-1-carboxylate was obtained (1.4 g, 3.09 mmol, 76% yield). MS (ESI, cation) m / z 475.1 (M + l) ⁺ .

Step 3: tert-butyl 4- (3-acetyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) piperazine-1-carboxyl Rate

Tert-butyl 4- (3-acetyl-4-(((trifluoromethyl) sulfonyl) oxy) phenyl) piperazine-1-carboxylate (1.17 g, 2.59 mmol), bis (pinacolato) diboron (1.642 g, 6.46 mmol), (1,1'-bis (diphenylphosphino) ferrocene) dichloropalladium (II) (0.189 g, 0.259 mmol), and potassium acetate (0.888 g, 9.05 mmol) A 25 mL single-necked round bottom flask was evacuated and backfilled with nitrogen over three cycles, followed by addition of 1,4-dioxane (12 mL). The resulting mixture under argon was placed in an oil bath and heated to 50 ° C. and stirred for 20 h under argon at this temperature. The temperature was lowered to 45 ° C. and the mixture was stirred at this temperature overnight. The crude reaction mixture was passed through a silica gel plug. The filtrate is concentrated in vacuo, the residue is dissolved in DCM and added to silica gel precolumn (25 g) and flash column chromatography using 24 g ISCO gold column eluting with 0% to 40% EtOAc in hexanes. Purified with tert-butyl 4- (3-acetyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) piperazine-1-carboxyl The rate was obtained as a solid (380 mg, 0.883 mmol, 34.1% yield). MS (ESI, cation) m / z 431.3 (M + l) ⁺ .

Step 4: 1- (5- (piperazin-1-yl) -2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) ethanone

Tert-butyl 4- (3-acetyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) piperazine-1-carboxylate in DCM Was treated with TFA to remove the Boc group. After concentration 1- (5- (piperazin-1-yl) -2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) ethanone Isolated and used without further purification. MS (ESI, cation) m / z 331.2 (M + l) ⁺ .

(2S) -N, N-bis (4-methoxybenzyl) -2-methylpent-4-ene-1-sulfonamide and (2R) -N, N-bis (4-methoxybenzyl) -2- Methyl-4-PENTENE-1-sulfonamide

The title compound was prepared from intermediate EE12 and pent-4-en-2-yl 4-methylbenzenesulfonate following a similar procedure described below.

(2R, 3R) -N, N-bis (4-methoxybenzyl) -3-methylhex-5-ene-2-sulfonamide and (2S, 3R) -N, N-bis (4-methoxybenzyl ) -3-methylhex-5-ene-2-sulfonamide

N, N-bis (4-methoxybenzyl) ethanesulfonamide (intermediate EE13; 1030 mg, 2.95 mmol) was azeotropically mixed with toluene for 2 hours under vacuum. Under argon, THF was added and the solution cooled to -78 ° C. Then N-butyllithium solution (2.5 M in hexane, 1.533 mL, 3.83 mmol) was added and the mixture was stirred at -78 ° C for 60 minutes. (S) -pent-4-en-2-yl 4-methylbenzenesulfonate (Prepared according to the procedure by Sigman, MS et al. J. Am. Chem. Soc. , 2012, 134 (28), 11408-11411) 1417 mg, 5.90 mmol) was added as a solution in 3 mL. Then THF was added. After 5 minutes, the mixture was warmed to ambient temperature and stirred overnight under argon. The mixture was quenched with saturated NH ₄ Cl, filtered with EtOAc, dried over MgSO ₄ and concentrated. Crude was injected into a SiO ₂ gel cartridge and purified by chromatography using a 40 g ISCO column eluting with 5% to 10% to 20% to 40% EtOAc in hexanes to give the title mixtures as a mixture in a 2.3: 1 ratio. Obtained (420 mg, 1.00 mmol, 34.1% yield).

Intermediate AA11A

(S) -6'-Chloro-5-(((1R, 2R) -2-((S) -1-hydroxyallyl) cyclobutyl) methyl) -3 ', 4,4', 5-tetrahydro -2H, 2'H-spiro [benzo [B] [1,4] oxazepine-3,1'-naphthalene] -7-carboxylic acid

Step 1: (R) -6-chloro-3,4-dihydro-2H-spiro [naphthalene-1,2'-oxirane] and (R) -6-chloro-3,4-dihydro-2H- Spiro [naphthalene-1,2'-oxirane]

In a 2 L four-necked round bottom flask (RBF) 6-chloro-3,4-dihydro-1 (2H) -taphthalenone (123 g, 681 mmol), trimethylsulfonium iodide (143 g, 701 mmol) , And DMSO (1100 mL) were charged. KOH (76 g, 1362 mmol) (pellet) was added. The suspension was stirred at ambient temperature for 2 days after which the crude ¹ H NMR showed no residual starting material. The solution was poured into 800 g of ground ice, then rinsed with MTBE (200 mL) and MTBE (700 mL) was added once more. After the resulting mixture was stirred and distributed for 5 minutes, the bottom aqueous layer was extracted twice with MTBE (500 mL, 300 mL) and combined with the main MTBE extract. The combined organic streams were washed with brine (2 × 600 mL) and 330 g Al ₂ O _{3 (} neutral) was added. The resulting suspension was stirred for 5 min at 22 ° C., after filtration, washed with MTBE (400 mL). The filtrate was concentrated to give the product as a red viscous oil (125 g, 94%).

Step 2: (S) -6-chloro-1,2,3,4-tetrahydronaphthalene-1-carbaldehyde and (R) -6-chloro-1,2,3,4-tetrahydronaphthalene-1- Carbaldehyde

3 L of three-necked RBF were charged with racemic 6-chloro-3,4-dihydro-2H-spiro [naphthalene-1,2'-oxirane] (160 g, 822 mmol) and THF (1760 mL). The batch was cooled to -8 ° C. in an IPA bath with dry ice, then boron fluoride diethyl etherate (5.07 mL, 41.1 mmol) was added over 3 minutes. The ash temperature was immediately raised to 10 ° C. through exotherm. The ash was stirred at −5 ° C. to 0 ° C. for 5 minutes and LC / MS analysis of the sample (quenched into cold NaHCO ₃ solution) showed complete conversion. The reaction was quenched by addition of saturated NaHCO ₃ (300 mL) at −5 ° C. followed by MTBE (400 mL) and the mixture was transferred to a separatory funnel and rinsed with MTBE (240 mL). After distribution, the aqueous layer was discarded with some white solid (such as boric acid or borax). The organic layer was washed with brine (350 mL) and concentrated under reduced pressure to give a red oil. The crude material was used directly in step 4.

Step 3: (6-Chloro-1,2,3,4-tetrahydronaphthalene-1,1-diyl) dimethanol

Racemic 6-chloro-1,2,3,4-tetrahydro-1-naphthalenecarbaldehyde was charged to 3 L three-necked RBF and rinsed with diethylene glycol (1000 mL). Formaldehyde (37% solution in H ₂ O; 652 mL, 8757 mmol) was added and the resulting biphasic emulsion was cooled to 5 ° C. with dry ice in an IPA bath. KOH (45% aqueous solution, 652 mL, 11.9 mol) was added over about 30 minutes and the temperature was kept below 20 ° C. Addition After the addition was complete, the ash (20 ° C.) was slowly heated to 45 ° C. (Note: exothermic reaction) and aged for 1 hour. HPLC showed complete conversion. Some viscous insoluble tar was formed, which was removed prior to aqueous workup. Brine (500 mL) was added to the ash and the mixture was extracted with DCM until the product content in the water phase was less than 5%. The combined DCM extracts were concentrated to 750 mL as a red oil, washed with H ₂ O (500 mL) and the product began to crystallize. Upon separation, the clear top water layer was discarded and the bottom layer was stirred for 30 min in an ice bath, filtered and washed with DCM (-100 mL) and H ₂ O (100 mL). The product was dried under dry air / vacuum to give a first crop (113 g, 498 mmol, 57% yield). The DCM layer of the resulting mother liquor was separated and concentrated to 200-300 g (KF = 0.5%), seeded and stirred in an ice bath for 30 minutes. The product was filtered, washed with DCM (50 mL) and dried in dry air / vacuum to give a total total yield of 6-chloro-1,2,3,4-tetrahydronaphthalene-1,1-diyl) dimethanol 127 A second crop was obtained against g (64%) (14.3 g, 63.1 mmol, 7% yield).

Step 4: (S)-(6-Chloro-1- (hydroxymethyl) -1,2,3,4-tetrahydronaphthalen-1-yl) methyl 4-bromobenzoate

2,6-bis ((R) -5,5-dibutyl-4-phenyl-4,5-dihydrooxazol-2-yl) pyridine ( R, R -strong catalyst in dry DCM (450 mL) To a solution of Kang Catalyst)) (1.57 g, 2.64 mmol), copper (II) chloride (0.355 g, 2.64 mmol) was added and the resulting green solution was stirred at room temperature for 1 hour. This solution was added via cannula to a solution of (6-chloro-1,2,3,4-tetrahydronaphthalene-1,1-diyl) dimethanol (30 g, 132.73 mmol) in dry DCM (800 mL). . The resulting mixture was cooled to −78 ° C., then a bright green precipitate was observed. Then a solution of 4-bromobenzoyl chloride (34.77 g, 158.79 mmol) in DCM (500 mL) was added slowly, followed by N-ethyl-N-isopropylpropan-2-amine (20 g, 154 mmol). Added dropwise. The resulting reaction mixture was stirred at −78 ° C. for 3 hours, then quenched with pH 3 phosphate buffer (1 L) and vigorously stirred to warm up to ambient temperature. The mixture was then diluted with DCM (2 L) and the layers separated. The organic phase was washed with pH 3 buffer (1 L), saturated NaHCO _{3 (} 1 L), and brine (2 L), which was then dried over Na ₂ SO ₄ , filtered and concentrated. The crude was purified by column chromatography using SiO ₂ gel (100-200 mesh, 80% DCM in hexane) to give pure (S)-(6-chloro-1- (hydroxymethyl) -1,2,3 , 4-tetrahydronaphthalen-1-yl) methyl 4-bromobenzoate was obtained (45 g, 84%; er = 91.4: 8.6). ChiralCel ^® OD-H (250 mm x 4.6 mm); Mobile phase: n-hexane: IPA: 90:10; Run time: 20 minutes; Flow rate: 1 mL / min; Sample manufacture: IPA. Retention time (main peak)-9.32 min; Retention time (incident peak)-11.46 minutes).

Step 5: (R)-(6-Chloro-1-formyl-1,2,3,4-tetrahydronaphthalen-1-yl) methyl 4-bromobenzoate

(S)-(6-Chloro-1- (hydroxymethyl) -1,2,3,4-tetrahydronaphthalen-1-yl) methyl 4-bromobenzoate (100 g, in DCM (2.5 L) 244.5 mmol) was added Dess-Martin periodinane (121.4 g, 293.3 mmol) at 10 ° C. After the addition the cooling bath was removed and the reaction mixture was stirred for 30 minutes at ambient temperature. Then H ₂ O (9 mL) was added and the resulting biphasic mixture was stirred at ambient temperature for 30 minutes. The reaction mixture was cooled to 0 ° C. and quenched with ₂ L of a 1: 1 mixture of 10% Na ₂ S ₂ O ₃ / saturated NaHCO ₃ solution. The reaction mixture was further stirred at ambient temperature for 10 minutes, then the layers were separated and the aqueous layer was extracted with EtOAc (2 x 1.5 L). The combined organic layers were washed with 1 L of 10% Na ₂ S ₂ O ₃ / saturated NaHCO ₃ solution and 1 L of brine, then dried over Na ₂ SO ₄ , filtered and concentrated. Purify the residue by column chromatography using SiO ₂ gel (100-200 mesh, 5% EtOAc / hexanes) to (R)-(6-chloro-1-formyl-1,2,3,4-tetrahydro Naphthalen-1-yl) methyl 4-bromobenzoate was obtained (80 g, 81%).

Enantiomeric purity of the title compound could be improved by the following procedure: (R)-(6-chloro-1-formyl-1,2,3,4-tetrahydronaphthalen-1-yl) methyl 4- Bromobenzoate (190 g) was added in toluene (950 mL) and heated to 50 ° C. for complete dissolution. The homogeneous solution was cooled to ambient temperature and seeded with the racemic compound. The solution was cooled to -25 ° C and aged overnight. The mother liquor is then poured and concentrated to give 160 g of (R)-(6-chloro-1-formyl-1,2,3,4-tetrahydronaphthalen-1-yl) methyl 4-bromobenzo enriched with enantiomers. Obtain was obtained (94% ee determined by chiral HPLC). Chiral HPLC conditions: column: ChiralCel ^® OD-H (250 mm x 4.6 mm); Mobile phase: n-hexane: IPA: 90:10. Running time: 20 minutes. Flow rate: 1 mL / min Sample preparation: ethanol. Retention time (main peak): 8.488 min (96.97%); Retention time (incident peak): 9.592 minutes (3.03%).

Step 6: (R)-(6-Chloro-1- (dimethoxymethyl) -1,2,3,4-tetrahydronaphthalen-1-yl) methanol

(R)-(6-Chloro-1-formyl-1,2,3,4-tetrahydronaphthalen-1-yl) methyl 4-bromobenzoate (75 g, 183.8 mmol) in anhydrous MeOH (1 L) To the solution of), p -TsOH (1 g, 9.2 mmol) and trimethyl orthoformate (58.4 mL, 551 mmol) were added and the reaction mixture was refluxed until the starting material was consumed completely (-4 hours). The reaction was concentrated to 50% volume and diluted with THF (1 L) and 1N NaOH (1 L, 1 mol). The resulting reaction mixture was stirred at 40 ° C. overnight and then concentrated under reduced pressure. The residue was diluted with EtOAc (1.5 L). The aqueous layer was separated and extracted with EtOAc (2 × 500 mL) and the combined organic layers were washed with 1N NaOH (1 L) and brine (1 L), dried over Na ₂ SO ₄ and concentrated under reduced pressure. The crude material was purified by column chromatography using a SiO ₂ gel (10% EtOAc / hexanes) of 100-200 mesh size and purified (R)-(6-chloro-1- (dimethoxymethyl) -1,2,3 , 4-tetrahydronaphthalen-1-yl) methanol was obtained as a light brown thick oil (44 g, 89%).

Step 7: tert-butyl-4-fluoro-3-nitrobenzoate

To a solution of 4-fluoro-3-nitrobenzoic acid (100 g, 540.2 mmol) in t-butanol (2.5 L) was diluted DMAP (13.18 g, 108.04 mmol) and ditert-butyl dicarbonate (248 mL, 1080.4 mmol). Was added and the reaction mixture was heated at 40 ° C. overnight. After completion, the reaction mixture was diluted with H ₂ O and the aqueous phase was extracted with EtOAc (3 × 1.5 L). The combined organic layers were further washed with H ₂ O (1 × 1 L), brine (1 × 1 L) and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure, and the crude material thus obtained was purified by column chromatography (eluted with a gradient of 100-200 mesh SiO ₂ gel, hexane 100% to 5% EtOAc in hexanes) and purified tert-butyl-. 4-Fluoro-3-nitrobenzoate was obtained as a light yellow solid (70 g, 54%).

Step 8: (R) -tert-butyl 4-((6-chloro-1- (dimethoxymethyl) -1,2,3,4-tetrahydronaphthalen-1-yl) methoxy) -3-nitrobenzo Eight

Solution of (R)-(6-chloro-1- (dimethoxymethyl) -1,2,3,4-tetrahydronaphthalen-1-yl) methanol (70 g, 259.2 mmol) in dry THF (3.5 L) Was cooled to 0 ° C. and LiHMDS (1M in THF; 363 mL, 363 mmol) was added dropwise. After 5 minutes, a solution of tert-butyl 4-fluoro-3-nitrobenzoate (74.9 g, 311 mmol) in THF (500 mL) was added dropwise through a dropping funnel and the resulting mixture was allowed to warm to ambient temperature. After completion (˜1 hour), the mixture was cooled to 0 ° C., quenched with saturated NH ₄ Cl solution (1 L) and extracted with EtOAc (3 × 1 L). The combined organic layers were washed with NH ₄ Cl (1 L) and brine (1 L), dried over Na ₂ SO ₄ and concentrated under reduced pressure. The crude material thus obtained was purified by column chromatography using SiO ₂ gel (5% EtOAc / hexanes) of 100-200 mesh size to give (R) -tert-butyl 4-((6-chloro-1- (dimethoxy). Methyl) -1,2,3,4-tetrahydronaphthalen-1-yl) methoxy) -3-nitrobenzoate was obtained as a yellow thick oil (110 g, 87% yield).

Step 9A: (R) -4-((6-chloro-1-formyl-1,2,3,4-tetrahydronaphthalen-1-yl) methoxy) -3-nitrobenzoic acid

(R) -tert-butyl 4-((6-chloro-1- (dimethoxymethyl) -1,2,3,4-tetrahydronaphthalen-1-yl) methoxy) -3 in MeCN (1 L) To a solution of nitrobenzoate (35 g, 71.25 mmol), erbium triflate (4.3 g, 7.1 mmol) and H ₂ O (13 mL) were added. The resulting mixture was heated to 80 ° C. overnight. The solvent was then removed under reduced pressure, and the residue was dissolved in Et ₂ O (1.5 L) and washed with 1N HCl (500 mL) and brine (500 mL). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated to give (R) -4-((6-chloro-1-formyl-1,2,3,4-tetrahydronaphthalen-1-yl) methoxy ) -3-nitrobenzoic acid was obtained (30 g), which was used without further purification.

Alternatively, (R) -4-((6-chloro-1-formyl-1,2,3,4-tetrahydronaphthalen-1-yl) methoxy) -3-benzoic acid is prepared as follows (step 4) (6-chloro-1,2,3,4-tetrahydronaphthalene-1,1-diyl) dimethanol:

Copper (II) chloride (0.095 g, 0.02 equiv), 2,6-bis ((R) -5,5-dibutyl-4-phenyl-4,5-dihydrooxazole- in 250 mL of three-necked RBF 2-yl) pyridine (0.42 g, 0.02 equiv) and THF (28.5 g, 4V) were charged. After inactivation with N ₂ , the ash was stirred at 20 ° C. for 0.5 h. In a homogeneous green solution, (6-chloro-1,2,3,4-tetrahydronaphthalene-1,1-diyl) dimethanol (8.0 g, 1.00 equiv) followed by THF (14.2 g, 2V) and 4-methyl Morpholine (3.75 g, 1.05 equiv) was added. The reaction mixture was cooled to −20 ° C. and a solution of 1-naphthoyl chloride (7.06 g, 1.05 equiv) in THF (21.3 g, 3 V) was added to the batch over 0.5 h and the temperature maintained below −15 ° C. It was. After aging for 20 hours at -20 ° C, an aliquot of the reaction slurry was sampled and analyzed by HPLC. While maintaining the temperature at -20 ° C, the slurry was filtered directly through a glass frit funnel. The filter cake was washed twice with cold THF (<10 ° C.) (2 × 14.2 g, 2V) and rinsed through the reaction vessel. The filter cake (4-methylmorpholine-HCl) was transferred to a labeled container. The mother liquor and wash were concentrated to a minimum volume and the distillation solvent was exchanged with toluene until the ash volume as measured by QNMR was 6 V and the toluene / THF ratio exceeded 98: 2 (v / v). Heptane (11 g, 2V) was added to the ash at 20 ° C. and the slurry was heated to 85 ° C. (where elution was observed). The solution was cooled to 75 ° C. and filled with seeds (0.27 g, 0.02 equiv). The slurry was cooled to 20 ° C. over 3 hours and aged for longer than 1 hour. The ash is filtered through a glass frit filter, the cake is washed with (3: 1 v / v) toluene / heptane (11 g, 2V) and then (1: 1 v / v) toluene / heptane (11 g) , 2V). The cake was dried under N ₂ at ambient temperature for 12 hours and analyzed dry by QNMR (<1 wt% toluene and heptane). The product was obtained as an off-white solid (8.75 g, 63% after weight control).

A 60 L jacketed reactor, ventilated using a bleach scrubber, was treated with (S)-(6-chloro-1- (hydroxymethyl) -1,2,3,4-tetrahydronaphthalen-1-yl) methyl 1-naphtho Eight (2.693 Kg, 88.6 wt%, 6.3 mol) followed by DCM (17.9 Kg, 5 vol) and EtN i Pr ₂ (2.84 Kg, 3.5 equiv). After inactivation with N ₂ , the ash was stirred and cooled to 0 ° C. A freshly prepared solution of sulfur trioxide pyridine (7.43 Kg, 2.10 Kg in 3 vol. DMSO, 2.5 equivalents sulfur trioxide pyridine) was added over 30 minutes to the alcohol slurry mixture in the reactor while maintaining the ash temperature below 15 ° C. After addition, HPLC analysis showed more than 99% conversion. The ash was quenched by adding H ₂ O (14 L, 5 vol) over about 20 minutes while maintaining the ash temperature below 15 ° C., then toluene (16.8 L, 6 vol) was added. After distribution, the organic layer was treated with H ₂ O (14 L, 5 vol) and toluene (16.8 L, 6 vol). The upper organic layer was washed twice with 2 N HCl (14 L, 5 vol each) and brine (14 L, 5 vol). The organic layer was poured out into a clean vessel, analyzed by HPLC, and then transferred back to the clean 60 L reactor through an inline filter. The ash was concentrated to a minimum volume and the solvent was converted to MeOH until the ash volume as measured by QNMR became 28 L (10 vol) and the MeOH / toluene ratio was 3: 1 (v / v). The ash was then transferred to a 30 L jacketed reactor through an inline filter. After the ash temperature was adjusted to 30 ° C., the ash was seeded with aldehyde (51 g, 0.02 equiv) as a slurry in MeOH (400 mL). After the slurry is aged at 30 ° C. for 30 minutes, the batch is solvent converted by distillation with MeOH until the batch volume is 11 L (4 vol) and the MeOH / toluene ratio is ≧ 99: 1 (v / v). I was. The ash is then cooled to 5 ° C. and a MeOH / H ₂ O mixture (3.70 Kg MeOH + 1.34 Kg H ₂ O) is added over 1.5 hours to bring the total solvent volume to approximately 5.5 vol, and the final MeOH / H ₂ O Was 90/10 (v / v). The ash was heated to 65 ° C. over 30 minutes, cooled to 20 ° C. over 2 hours and aged for about 2 hours. The batch was filtered through a filter Aurora ^® fitting over Kwacheon of ≤ 25 μm. The cake was washed with MeOH / H ₂ O (10: 1) (1 × 2 vol) and then with MeOH / H ₂ O (2: 1) (1 × 2 vol). The cake was dried under N ₂ at ambient temperature for at least 4 hours until dry to give the product as an off-white solid (1.99 Kg, 72% after wt% control).

Three-necked 250 mL RBF was added to (R)-(6-chloro-1-formyl-1,2,3,4-tetrahydronaphthalen-1-yl) methyl 1-naphthoate (10 g, 94.4 wt%, 95.3 % LCAP, 99% ee), methanol (100 mL), trimethyl orthoformate (7 mL) and TsOH.H 2 O (0.24 g). RBF was inactivated with N2 and stirring was started. The ash was heated to 60 ° C. and aged for 2 hours. HPLC analysis showed at least 98% conversion.

The ash was concentrated using a rotary evaporator under vacuum (about 150-190 torr, external temperature approximately 40 ° C.) until the minimum volume. The ash was converted to THF by filling THF three times (50 mL each time) and distilling under vacuum (approx. 165 Torr, external temperature approximately 40 ° C.). After each of the first two THF charges, the ash was concentrated to a minimum volume and QNMR analysis of the sample after the last THF charge and distillation showed a target ratio of THF / MeOH (v / v) of> 20/1. LiOHH ₂ O (10.46 g, 10 equiv) and H ₂ O (50 mL) were charged to three balls of 250 mL RBF. The reaction mixture was heated to 60 ° C. and aged for 18 hours. HPLC analysis showed> 99% conversion. The ash was cooled to 20 ° C. and transferred to a 500 mL separatory funnel. MTBE (106 mL) was charged into a separatory funnel and the funnel was shaken well. After 5 minutes, the bottom water layer was drained. The upper organic layer was washed twice with 20% K ₂ CO ₃ (32 mL and 11 mL). The ash was transferred to 250 mL of RBF. Analysis by HPLC showed less than 2% naphtanic acid byproducts. The ash was concentrated to a minimum volume using a rotary evaporator (300 mbar, external temperature approximately 40 ° C.) at reduced pressure. The ash was converted to THF by adding and distilling THF (˜50 mL, ˜50 mL) using a rotary evaporator (˜250 mbar, external temperature approximately ˜40 ° C.). After each THF charge was made, the ash was distilled out to a minimum volume. 250 mL of RBF was charged with THF (50 mL). KF of the sample showed 0% H ₂ O (0.1% or less acceptable). The ash was subjected to abrasive filtration (60 mL mid-frit funnel) into 250 mL of three-necked RBF which was transparent and dried using THF (50 mL) for rinsing and volume control. To the batch is added 4-fluoro-3-nitrobenzoic acid (4.61 g, 1.0 equiv), the mixture is cooled to -20 ° C and 20% potassium tert-butoxide THF solution (40 mL) is added over 1.5 hours The ash temperature was maintained at -20 ± 10 ° C (exothermic). After the addition was complete, the ash was aged at -20 ° C and aliquots analyzed by HPLC after 98 hours showed 98% conversion. Saturated NH ₄ Cl solution (10 mL) was added to the ash in the flask and the temperature was maintained at -20 ± 10 ° C, followed by H ₂ O (20 mL) and MeTHF (34 mL) at -20 ± 10 ° C. Was added. The mixture was warmed to 20 ° C. and stirred for 13 h. The ash was transferred to a separatory funnel and settled for about 5 minutes and the bottom water layer was removed while keeping the rag with the organic stream. The top organic stream was washed at 20 ° C. with saturated NH ₄ Cl solution (10 mL) and H ₂ O (20 mL). After sinking for about 5 minutes, the aqueous layer was separated. MSA (4 mL) was added to the total crude organic stream (KF = 14%) in 250 mL three-neck RBF. The batch was heated to reflux for 25 hours (65 ° C.) and LC analysis showed complete conversion (≧ 97%).

The ash was cooled to <20 ° C. and K ₃ PO ₄ H ₂ O (4.5 g) and H ₂ O (7 mL) were added. The ash was transferred to a separatory funnel and poured along the bottom water layer to give a crude solution of the aldehyde product. The combined crude organic streams were concentrated to a minimum volume using a rotary evaporator. The ash contained in 500 mL of RBF was charged with AcOH (˜50 mL, ˜50 mL) and distilled using a rotary evaporator at reduced pressure (30 mbar, external temperature approximately 40 ° C.). THF levels were measured by QNMR, but nothing was observed. The mixture was transferred to 250 mL of 3-neck RBF and the total volume was adjusted to about 40 mL by the addition of AcOH when crystallization took place. To the batch was added H ₂ O (12 mL) over about 1 hour. After aging for more than 1 hour, the supernatant concentration by LC analysis was 9 mg / mL. If the concentration is above 10 mg / mL, a small amount of H ₂ O (0.2 vol) can be added; After confirmation by LC, repeat if necessary. The ash was filtered off, washed with 20% H ₂ O / AcOH (23 mL) and dried under N ₂ / vacuum for 3.25 hours to give the title compound (8.22 g) as an off-white solid (yield corrected to purity 82%). ).

Step 9B: (R) -tert butyl 4-((6-chloro-1-formyl-1,2,3,4-tetrahydronaphthalen-1-yl) methoxy) -3-nitrobenzoate

(R) -tert-butyl 4-((6-chloro-1- (dimethoxymethyl) -1,2,3,4-tetrahydronaphthalen-1-yl) methoxy)-in anhydrous acetone (41 mL)- 3-nitrobenzoate to a solution of amberlyst ^® -15 (1g, 2.033 mmol); the (1g, 2.033 mmol together once pre-washing with anhydrous acetone 10 mL) was added. The mixture was heated to 50 ° C. for 3.5 h, then filtered and rinsed with DCM. The filtrate was concentrated and dried overnight (high red) under high vacuum. LC / MS and NMR analysis indicated that 0.5 equivalents of methyl oxide were present as well as ˜10% of the corresponding carboxylic acid. The mixture proceeded to step 11 without further purification.

Step 10: (S) -6'-Chloro-3 ', 4,4', 5-tetrahydro-2H, 2'H-spiro [benzo [B] [1,4] oxazepine-3,1'- Naphthalene] -7-carboxylic acid

Crude (R) -4-((6-chloro-1-formyl-1,2,3,4-tetrahydronaphthalen-1-yl) methoxy) -3-nitrobenzoic acid in AcOH (1 L) 30 g, 77.10 mmol) was heated to 70 ° C. and iron powder (28 g, 500 mmol) was added. The resulting mixture was heated at 70 ° C. for ˜ 4 hours. AcOH was then removed under reduced pressure and the residue was dissolved in DCE (1 L). Sodium triacetoxy borohydride (46.5 g, 740 mmol) was added once and the reaction mixture was stirred at ambient temperature for 1 hour. The reaction was then quenched with H ₂ O followed by 10% aqueous citric acid (500 mL). The aqueous phase was extracted with DCM (2 × 1 L) and the combined organic layers were washed with brine (500 mL), dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by column chromatography using SiO ₂ gel (40% EtOAc / hexanes) in 100-200 mesh size to pure (S) -6'-chloro-3 ', 4,4', 5-tetrahydro- 2H, 2'H-spiro [benzo [b] [1,4] oxazepine-3,1'-naphthalene] -7-carboxylic acid was obtained as a white solid (24 g, 99% after two steps).

Alternatively, (S) -6'-chloro-3 ', 4,4', 5-tetrahydro-2H, 2'H-spiro [benzo [b] [1,4] oxazepine-3,1 ' -Naphthalene] -7-carboxylic acid with ((1S, 4R) -7,7-dimethyl-2-oxobicyclo [2.2.1] heptan-1-yl) methanesulfonic acid (1: 1) Prepared as follows:

In a pressure reactor (R) -4-((6-chloro-1-formyl-1,2,3,4-tetrahydronaphthalen-1-yl) methoxy) -3-nitrobenzoic acid (20 g, 94 wt %), Wet 5% Pt / S / C (2.2 g), THF (400 mL) and titanium isopropoxide (0.5 mL). The reactor was sealed, purged with inert gas (3 cycles, at least 1 cycle was stirred) and then purged with H ₂ (1 cycle). The reactor was pressurized to 70 psig with H ₂ , stirring (950 rpm) was initiated, and the temperature was raised to 90 ° C. to maintain H ₂ pressure in the reactor (70 psig at 22-30 ° C., 50-60 ° C.). 80 psig, and 90 psig at 88-91 ° C.). After 16 hours, the reactor was cooled to ambient temperature and then purged with inert gas (3 cycles). HPLC analysis of the reaction confirmed a conversion above 98%.

The reaction mixture was filtered through Celite ^®, Pat (2 in.) Using the additional THF to rinse and concentrated at 40 ℃ the filtrate under reduced pressure. To the residue was added IPA (60 mL) and 2-4% aqueous MeOH (10 mL). Mixture for 10 minutes, and then, filtered through a Celite ^® pad (2 in.) Was stirred. MeOH was evaporated at 40 ° C. under reduced pressure and a solution of + CSA (56.0 g) in IPA (200 mL) was added dropwise over 2 hours to an IPA concentrate cooled to ambient temperature. After 10% in CSA solution was added, the mixture was seeded with crystals (10-15 mg) of the title compound, followed by addition of the remaining CSA solution. After stirring overnight at ambient temperature, the mixture was filtered, the filter cake was washed with 100 mL of IPA and dried at ambient temperature under vacuum / N ₂ . The product is (S) -6'-chloro-3 ', 4,4', 5-tetrahydro-2H, 2'H-spiro [benzo [b] [1,4] oxazepine-3,1'-naphthalene ] -7-carboxylic acid and ((1S, 4R) -7,7-dimethyl-2-oxobicyclo [2.2.1] heptan-1-yl) methanesulfonic acid are isolated as white solids in a 1: 1 ratio ( 85-88% yield,> 99.5% ee).

Step 11A: (S) -Methyl 6'-chloro-3 ', 4,4', 5-tetrahydro-2H, 2'H-spiro [benzo [B] [1,4] oxazepine-3,1 ' Naphthalene] -7-carboxylate

(S) -6'-chloro-3 ', 4,4', 5-tetrahydro-2H, 2'H-spiro [benzo [b] [1,4] oxazepine-3 in methanol (6 L), by the addition of 1,1'-naphthalene] 7-carboxylic acid (130 g, 379 mmol) amberlyst ® -15 (130 g, also pre-washed with anhydrous methanol) was added in, and heated and refluxed for 10 hours. Then amberlyst ^®- 15 was removed by filtration and washed with methanol (3 x 300 mL). The combined filtrates were concentrated and the residue was purified by column chromatography to give pure (S) -methyl 6'-chloro-3 ', 4,4', 5-tetrahydro-2H, 2'H-spiro [benzo [ b] [1,4] oxazepine-3,1'-naphthalene] -7-carboxylate was obtained as a white solid (105 g, 77%). Chiral HPLC conditions: column: ChiralCel ^® OD-H (250 mm x 4.6 mm, 5 m); Mobile phase: n-hexane: EtOH: 95:05. Running time: 25 minutes. Flow rate: 1 mL / min retention time (incident peak): 10.162 min (1.98%); Retention time (major peak): 12.292 minutes (98.02%).

Step 11B: (S) -tertbutyl 6'-chloro-3 ', 4,4', 5-tetrahydro-2H, 2'H-spiro [benzo [B] [1,4] oxazepine-3,1 '-Naphthalene] -7-carboxylate

(R) -tert-butyl 4-((6-chloro-1-formyl-1,2,3,4-tetrahydronaphthalen-1-yl) methoxy) -3 in AcOH (20.22 mL, 353 mmol) To a solution of nitrobenzoate (0.9 g, 2.018 mmol) was added iron (0.676 g, 12.11 mmol) at 70 ° C. The mixture was stirred vigorously for 4 hours, then concentrated and the residue was diluted with 20 mL of 1,2-DCE. Sodium triacetoxy hydroborate (1.711 g, 8.07 mmol) was added and the mixture was stirred at ambient temperature for 20 minutes. After quenching by addition of 20 mL H ₂ O, a thick slurry was formed. After addition of 20 mL of 10% citric acid solution, the mixture became lighter in color. The layers were separated and the aqueous layer was extracted with 2 x 20 mL DCM. The combined organics were washed with 10 mL 10% citric acid and 10 mL brine, dried over MgSO ₄ , filtered and concentrated. Precipitate the residue on a 3 g SiO ₂ gel and purify with 5-10% EtOAc in hexane to give (S) -tert-butyl 6'-chloro-3 ', 4,4', 5-tetrahydro-2H, 2'H-spiro [benzo [b] [1,4] oxazepine-3,1'-naphthalene] -7-carboxylate was obtained (557 mg, 1.393 mmol, 69.0% yield). Further eluting with 30% EtOAc in hexanes gave (S) -6'-chloro-3 ', 4,4', 5-tetrahydro-2H, 2'H-spiro [benzo [b] [1,4] oxazepine -3,1'-naphthalene] -7-carboxylic acid was obtained (132 mg, 0.384 mmol, 19.02% yield).

Step 12: (1R, 2S) -1,2-cyclobutanediyldimethanol

In a rapid stirred solution of LAH (1.0 M solution in THF, 1000 mL, 1000 mmol) in 3000 mL of three-necked RBF at argon stream at ambient temperature, solid (1R, 5S) -3-oxabicyclo [3.2. 0] heptane-2,4-dione (40 g, 317 mmol) was added gradually over 2 hours and the internal temperature of the reaction mixture was kept below 50 ° C. The reaction was stirred overnight at ambient temperature under argon. After 16 h, the reaction mixture was cooled twos ice to 10 ℃, under high-speed stream of argon, to a temperature of approximately 1 mL / min is maintained between 12 ~ 15 ℃, with vigorous stirring a H ₂ O solution of 36 mL ( 500 rpm) was added dropwise with an addition funnel. Then, the mixture was stirred vigorously (at 500 rpm) for 1 hour in an ice bath, then taken out of the ice bath and stirred for 1 hour at room temperature, and then cooled again to 5-10 ° C. in an ice bath. To the mixture was added 36 mL of 15% NaOH aqueous solution over 45 minutes and maintained at a temperature of 10-20 ° C. 108 mL of H ₂ O was added dropwise to the mixture over an hour by an addition funnel while maintaining the temperature at 10-20 ° C. After the addition of H ₂ O was completed, the flask was taken out of the ice bath to equilibrate to room temperature and vigorously stirred under argon overnight. After stirring for 16 hours, the mixture was filtered and the filtrate was concentrated under reduced pressure to give a colorless, slightly opaque oil. The oil was dissolved in Et ₂ O, stirred over anhydrous MgSO ₄ , and filtered through a pad of Celite ^® . The filtrate was concentrated under reduced pressure to afford 32.8 g of a colorless oil which was used in the next step without further purification (89% yield).

Step 13: cis -cyclobutane-1,2-diylbis (methylene) diacetate

Ac ₂ O (2.59 mL; 3.0 equiv) was added to cis -1,2-cyclobutanediyldimethanol (1.06 g, 9.15 mmol) and the resulting solution was heated to 50 ° C. After stirring overnight, the mixture was analyzed by GC, indicating complete conversion. The mixture was then diluted with 15 mL of heptane and concentrated in vacuo to give a clear oil. The oil was dissolved in 15 mL heptane and concentrated again to oil (to remove Ac ₂ O by azeotropic mixing) to give the title compound as an oil (1.827 g, 88% yield, QNMR using benzyl benzoate as internal standard) Purity by 88.3%).

Step 14: ((1R, 2S) -2- (hydroxymethyl) cyclobutyl) methyl acetate

1 M sodium citrate solution (prepared by mixing sodium citrate tribasic dihydrate; 682 g, 2320 mmol) and H ₂ O were charged to a total volume of approximately 2.3 L in a 12 L three-necked RBF equipped with a mechanical stirrer, 3.48 L of H ₂ O (-25 ° C.) was charged. The mixture was cooled to approximately 20.2 ° C. using an ice bath. pH ~ 8.46 (measured with pH probe). Thereafter, amano lipase (41.8 g, 1547 mmol) from Pseudomonas fluorescens was charged once (pH-8.12) and the mixture was stirred vigorously at ambient temperature for ˜ 5 minutes. (1R, 2S) -cyclobutane-1,2-diylbis (methylene) diacetate (348 g, 1547 mmol) was added once and the resulting mixture was vigorously stirred at ambient temperature while monitoring the internal temperature and pH. After the mixture was stirred overnight (˜20.9 ° C. and pH˜5.45), an aliquot was collected, extracted with IPAc, diluted with MeCN, analyzed by GC, and the reaction was considered complete (1.21% SM residue, 0.17% enantiomer, 1.8% diol). Celite ^® (70 g) was added to the reaction mixture and the slurry was filtered through a Celite ^® pad on a medium porous glass filter (quick filtration, 15-20 min) and rinsed with 2.5 L of IPA. The biphasic mixture was transferred to 12 L extractor and stirred for 1 minute. The aqueous layer was separated and extracted with IPAc (1 × 4 L), and the combined organic extracts were concentrated in vacuo to give 337.28 g (99.6% ee ; about 50-60 mol% residual IPA by ¹ HNMR; QNMR: 37.63 mg + Benzyl benzoate (Aldrich Cat. No. B6630, Lot No. MKBG9990V, 61.27 mg; Results: ˜65 wt%; Corrected yield 89%) The crude product was used as is in the next step.

Step 15: ((1R, 2R) -2-formylcyclobutyl) methyl acetate

2 L Atlas reactor was charged with ((1R, 2S) -2- (hydroxymethyl) cyclobutyl) methyl acetate (126.39 g, 79.6 wt% by QNMR; 636 mmol) and 1 L DCM and jacketed The temperature was set to 20 ° C. Iodinebenzene diacetate (225 g, 700 mmol) was added as a solid (endothermic addition: temperature dropped to 15 ° C). TEMPO (3.97 g, 25.4 mmol) was added in one portion as a solid to give a cloudy orange solution which turned to a clear color after 20 minutes. After stirring at 20 ° C. overnight, an aliquot was collected, diluted with MeOH and analyzed by GC. If necessary, an additional kicker charge of iodinebenzene diacetate and TEMPO can be used to facilitate the completion of the reaction. The reaction mixture was then cooled to 1.8 ° C. (internal temperature, / water bath) and DIPEA (194 mL, 1113 mol) was added dropwise through an addition funnel over 65 minutes while maintaining the internal temperature below 5 ° C. The cooling bath was removed and the mixture was allowed to warm up to ambient temperature through stirring. After 48 hours an aliquot was collected, diluted with methanol and analyzed by GC, indicating a 12: 1 ratio of trans: cis isomer. The reaction mixture was then cooled to below 5 ° C. (ice bath) and H ₂ O (230 mL) was added over approximately 10 minutes (internal temperature reached 14 ° C.). The organic layer was separated, washed with H ₂ O (125 mL) and 1M aqueous NaH ₂ PO ₄ (90 mL), and concentrated in vacuo to give 273.4 g of ((1R, 2R) -2-formylcyclobutyl) methyl acetate. Obtained (QNMR: 68.85 mg + benzyl benzoate (Aldrich catalog number B6630, lot number MKBG9990V, 72.36 mg). The crude product was used as is in the next step.

Step 16: ((1R, 2R) -2-((R)-(1H-Benzo [D] [1,2,3] triazol-1-yl) (hydroxy) methyl) cyclobutyl) methyl acetate

To a solution of crude ((1R, 2R) -2-formylcyclobutyl) methyl acetate (5 g, 10.27 mmol) in 8 mL MTBE was added benzotriazole (1.296 g, 10.00 mmol) as a solid (slightly exotherm). castle). The clear solution became turbid and a precipitate formed. The mixture was equilibrated overnight at ambient temperature, then heptane (6 mL) was added. After aging for 6 hours, the mixture was filtered at ambient temperature and washed with 10 mL of 1: 1 MTBE / heptane. The white solid was air dried on frit under vacuum to give 2.48 g of ((1R, 2R) -2-((R)-(1H-benzo [d] [1,2,3] triazol-1-yl) (hydr) Oxy) methyl) cyclobutyl) methyl acetate was obtained.

Step 17: (S) -Methyl 5-(((1S, 2R) -2-acetoxycyclobutyl) methyl) -6'-chloro-3 ', 4,4', 5-tetrahydro-2H, 2 ' H-spiro [benzo [B] [1,4] oxazepine-3,1'-naphthalene] -7-carboxylate

(S) -Methyl 6'-chloro-3 ', 4,4', 5-tetrahydro-2H, 2'H-spiro [benzo [b] [1,4 in DCM (78 mL) ] Oxazepine-3,1'-naphthalene] -7-carboxylate (5.0 g, 13.97 mmol) in a solution of AcOH (38.8 mL) (from step 16) ((1R, 2R) -2-formylcyclobutyl Methyl acetate (4.36 g, 27.9 mmol) was added. The solution was stirred at ambient temperature for 10 minutes and then cooled to 0 ° C. and sodium cionborohydride (1.463 mL, 27.9 mmol) was added slowly over 1 hour. The mixture was stirred at 0 ° C. for 10 min, then slowly poured into cold NaOH solution and extracted with EtOAc (120 mL). The organic phase was washed with brine, dried over anhydrous Na ₂ S0 ₄ and concentrated. The residue was added to 220 g ISCO gold column and eluted with 0% to 10% EtOAc / hexanes to give 6.0 g of the title compound as a white solid. m / z (ESI cation) 498.1 (M + H) ⁺ .

Step 18A: (S) -Methyl 6'-Chloro-5-(((1R, 2R) -2- (hydroxymethyl) cyclbutyl) methyl) -3 ', 4,4', 5-tetrahydro- 2H, 2'H-spiro [benzo [B] [1,4] oxazepine-3,1'-naphthalene] -7-carboxylate

(S) -methyl 5-(((1R, 2S) -2- (acetoxymethyl) cyclobutyl) methyl) -6'-chloro-3 ', 4,4 in MeOH (99 mL) KOH in a solution of ', 5-tetrahydro-2H, 2'H-spiro [benzo [b] [1,4] oxazepine-3,1'-naphthalene] -7-carboxylate (1.530 g, 3.07 mmol) (0.278 mL, 10.14 mmol) was added. The mixture was stirred at ambient temperature for 4 hours, then neutralized with 1N HCl to pH = 7 and concentrated under reduced pressure. The aqueous residue was extracted with EtOAc (400 mL), the organic extracts were washed with brine, dried over anhydrous Na ₂ SO ₄ and filtered through a short plug of SiO ₂ gel to afford the title compound as a white solid. (1.354 g obtained. M / z (ESI, cation) 456.2 (M + H) ⁺ )

Alternatively, (S) -methyl 6'-chloro-5-(((1R, 2R) -2- (hydroxymethyl) cyclobutyl) methyl) -3 ', 4,4', 5-tetrahydro -2H, 2'H-spiro [benzo [b] [1,4] oxazepine-3,1'-naphthalene] -7-carboxylate can be prepared as follows:

(S) -6'-Chloro-3 ', 4,4', 5-tetrahydro-2H, 2'H-spiro [benzo [b] [1,4] oxazepine-3,1 '-Naphthalene] -7-carboxylic acid with ((1S, 4R) -7,7-dimethyl-2-oxobicyclo [2.2.1] heptan-1-yl) methanesulfonic acid (1: 1 ratio; 32.22 g, 52.5 mmol) and (from step 17) ((1R, 2R) -2-((R)-(1H-benzo [d] [1,2,3] triazole) in DCM (226 mL, 7 mL / g) To a slurry of -1-yl) (hydroxy) methyl) cyclobutyl) methyl acetate (15.89 g, 57.7 mmol) was added sodium triacetoxy borohydride (13.90 g, 65.6 mmol) four times over 30 minutes. ((1R, 2R) -2-((R)-(1H-benzo [d] [1,2,3] triazol-1-yl) (2) to induce reaction completion (as determined by HPLC analysis) Hydroxy) methyl) cyclobutyl) methyl acetate (2.89 g, 10.50 mmol) and sodium triacetoxyborohydride (2.78 g, 13.12 mmol) were further added. Then 80 mL of H ₂ O was added and the resulting mixture was stirred for 5 minutes. The layers were separated and the organic phase was washed with 60 mL of H ₂ O and 20 mL of brine, then concentrated under reduced pressure to an oil. The residue was dissolved in 50 mL of MeOH and then 40 mL of 5N NaOH was added at ambient temperature (pyrogenic). After completion of the reaction (determined by HPLC analysis), the reaction mixture was partitioned between 133 mL of MTBE and 35 mL of 1.5 M citric acid. The organic phase was transferred to RBF and the solvent was exchanged for MeCN via atmospheric distillation. This solution was seeded at 62 ° C. (slurry was generated), allowed to reach ambient temperature and then aged overnight. The slurry was filtered through a coarse frit glass sinter funnel at 20.5 ° C. and the filter cake was washed with 60 mL of MeCN and then dried in a vacuum oven at 40 ° C. to constant weight. Final mass: 21.87 g (96.4 weight% by HPLC).

(S) -6'-Chloro-5-(((1R, 2R) -2- (hydroxymethyl) cyclbutyl) methyl) -3 ', 4,4', 5-tetra in 100 mL 3-neck RBF Hydro-2H, 2'H-spiro [benzo [b] [1,4] oxazepine-3,1'-naphthalene] -7-carboxylic acid (4.53 g, 1.0 equiv), MeOH (45 mL, 10 vol) After filling, the prepared SOCl ₂ solution (11.28 mL, 1.0 M in MeCN, 1.1 equiv) was charged. Under N ₂ atmosphere, the ash was heated to 55 ° C. and then stirred for 18 hours (or until conversion above 99% as determined by HPLC). The reaction mixture was then heated to 20 ° C. over 2 hours. Hunig base (3.94 mL, 2.2 equiv) was added to the resulting white slurry and aged for 0.5 h, then H ₂ O (9.0 mL, 2 V) was added as antisolvent over 1 h. The white slurry is aged for over 2 hours, the ash is filtered through a glass frit filter, the cake is washed with MeOH / H ₂ O (5: 1 v / v) (9.0 mL, 2V) and then MeOH / H ₂ O Washed with (2: 1 v / v) (9.0 mL, 2V). The cake was dried for 12 h at ambient temperature using vacuum under N ₂ . The product was obtained as a white solid (4.36 g, 92% yield).

Step 18B: (S) -tertbutyl 6'-chloro-5-(((1R, 2R) -2- (hydroxymethyl) cyclobutyl) methyl) -3 ', 4,4', 5-tetrahydro- 2H, 2'H-spiro [benzo [B] [1,4] oxazepine-3,1'-naphthalene] -7-carboxylate

(S) -tertbutyl 6'-chloro-3 ', 4,4', 5-tetrahydro-2H, 2'H-spiro [benzo [according to the procedure described for intermediate AA11A (of steps 18-19A) b] The title compound was synthesized from [1,4] oxazepine-3,1'-naphthalene] -7-carboxylate (intermediate AA11A, step 12B).

Step 19A: (S) -Methyl 6'-chloro-5-(((1R, 2R) -2-formylcyclobutyl) methyl) -3 ', 4,4', 5-tetrahydro-2H, 2 ' H-spiro [benzo [B] [1,4] oxazepine-3,1'-naphthalene] -7-carboxylate

Oxalyl chloride (26.1 mL, 1.0 in DCM) in a cooled (-70 ° C) solution of DMSO (7.12 mL, 2.5 equiv) and DCM (183 mL, 10 vol) in 1 L three-neck RBF inactivated with N ₂ M, 1.3 equiv.) Was added at a rate maintaining a temperature below −70 ° C. The ash was aged at -70 ° C for 30 minutes and then (S) -methyl 6'-chloro-5-((((1R, 2R)-) prepared in DCM (183 mL, 10 vol) (in step 19A). 2- (hydroxymethyl) cyclobutyl) methyl) -3 ', 4,4', 5-tetrahydro-2H, 2'H-spiro [benzo [b] [1,4] oxazepine-3,1 ' A solution of -naphthalene] -7-carboxylate (18.3 g, 1.0 equiv) was added at a rate maintaining the reaction temperature below -70 ° C. The ash was aged for 1.5 hours and then Et 3 N (22.4 mL, 4.0 equiv) was added at a rate to maintain the ash temperature below −70 ° C. After aging for 1 hour, the ash was warmed to -20 ° C and H ₂ O (366 mL, 20 vol) was added. The batch was stirred at 20 ° C. to separate the phases. The organic layer was washed with 2 x 1N HCl (183 mL, 10 vol) and brine (183 mL, 10 vol). The organic layer was abrasively filtered and concentrated in vacuo to afford (S) -methyl 6'-chloro-5-(((1R, 2R) -2-formylcyclobutyl) methyl) -3 ', 4,4', 5-tetra Hydro-2H, 2'H-spiro [benzo [b] [1,4] oxazepine-3,1'-naphthalene] -7-carboxylate was obtained as a tan foam (corrected for 19.91 g, wt%). Yield 94%).

Step 19B: (S) -tertbutyl 6'-chloro-5-(((1R, 2R) -2-formylcyclobutyl) methyl) -3 ', 4,4', 5-tetrahydro-2H, 2 'H-spiro [benzo [B] [1,4] oxazepine-3,1'-naphthalene] -7-carboxylate

(S) -tertbutyl 6'-chloro-5-(((1R, 2R) -2- (hydroxymethyl) cyclobutyl) methyl (in step 19B) following the procedure described for intermediate AA11A in step 20A ) -3 ', 4,4', 5-tetrahydro-2H, 2'H-spiro [benzo [b] [1,4] oxazepine-3,1'-naphthalene] -7-carboxylate (intermediate AA The title compound was synthesized from 11A).

Step 20: (S) -Methyl 6'-chloro-5-(((1R, 2R) -2-((S) -1-hydroxyallyl) cyclobutyl) methyl) -3 ', 4,4', 5-tetrahydro-2H, 2'H-spiro [benzo [B] [1,4] oxazepine-3,1'-naphthalene] -7-carboxylate

Oven dried 3-neck RBF, equipped with a pressure equilibration addition funnel, thermocouple and magnetic stir bar, was cooled to ambient temperature under purging of argon gas. (1R, 2S) -2-morpholino-1-phenylpropan-1-ol (40.2 g, 182 mmol; Brubaker, JD; Myers, AG Org. Lett . 2007, 9, 3523-3525 using positive pressure argon) Prepared according to the literature procedure). The addition funnel was filled with toluene (450 mL) and it was dropped into the reactor. The solution was cooled in an ethylene glycol-CO ₂ bath (˜-12 ° C.) and treated with a butyllithium solution (2.5 M in hexane, 72.6 mL, 182 mmol) to precipitate a white solid which stirred over 30 minutes. Gradually turned into a solution. Divinyl zinc solution (605 mL, 182 mmol; Brubaker, JD; Myers, AG Org. Lett. 2007, 9, 3523-3525 ) The concentration of divinyl zinc solution is determined by titration with iodine (Krasovskiy, A .; Knochel, P. Synthesis 2006, 890-891); the concentration was typically ˜0.25 M) and the solution was aged with stirring for 1 hour in an ice bath; Internal temperature was -15 ° C. (S) -Methyl 6'-chloro-5-(((1R, 2R) -2-formylcyclobutyl) methyl) -3 ', 4,4', 5-tetrahydro-2H, of step 20A, 2'H-spiro [benzo [b] [1,4] oxazepine-3,1'-naphthalene] -7-carboxylate (48.5 g, 107 mmol) (twice azeotrope with toluene) via cannula The solution was added over approximately 20 minutes as a solution in toluene (200 mL, 150 mL + 2 × 25 mL cannula / vial rinse). The internal temperature was raised to -10 ° C. The mixture was stirred for 90 minutes while maintaining the internal reaction temperature below -5 ° C. The reaction was quenched by filling the addition funnel with 30% w / w aqueous citric acid (450 mL) and then adding the solution to the reaction mixture. The reactor was removed from the bath and stirred at ambient temperature. The solution was transferred to a separatory funnel and the flask was rinsed with toluene and 30% aqueous citric acid (50 mL each). The layers were mixed and then separated. The organic layer was washed with H ₂ O (250 mL) then brine (250 mL) and finally dried over MgSO ₄ . The solution was filtered and concentrated to give a yellow oil (˜90 g after vacuum overnight, 20: 1 dr). It was divided into three batches and purified by column chromatography (10% to 20% EtOAc in hexanes; 1.5 kg SiO ₂ ) to give (S) -methyl-6'-chloro-5-(((1 R , 2 R ) -2-((S) -1-hydroxyallyl) cyclobutyl) methyl) -3 ', 4,4', 5-tetrahydro-2H, 2'H-spiro [benzo [b] [1,4] Oxazepine-3,1'-naphthalene] -7-carboxylate was obtained (43.3 g, 84%). The aqueous layer and washes were placed in an ice bath and basified to pH> 13 by addition of 8N aqueous NaOH. This solution was then extracted with toluene (3 × 250 mL). The combined organic extracts were washed with H ₂ O (250 mL) and brine (250 mL) and then dried over MgSO ₄ . The solution was filtered and concentrated to recover the ligand in yield> 95%.

Step 21: (S) -6'-Chloro-5-(((1R, 2R) -2-((S) -1-hydroxyallyl) cyclobutyl) methyl) -3 ', 4,4', 5 Tetrahydro-2H, 2'H-spiro [benzo [B] [1,4] oxazepine-3,1'-naphthalene] -7-carboxylic acid

(S) -methyl 6'-chloro-5-(((1R, 2R) -2- (in step 21) in a mixture of THF (18 mL), MeOH (6.00 mL) and H ₂ O (6.00 mL) (S) -1-hydroxyallyl) cyclobutyl) methyl) -3 ', 4,4', 5-tetrahydro-2H, 2'H-spiro [benzo [b] [1,4] oxazepine-3 To a solution of, 1'-naphthalene] -7-carboxylate (4.59 g, 9.52 mmol) was added LiOH.H ₂ O (0.799 g, 19.05 mmol) and the reaction stirred at 50 ° C. for 4 hours. The reaction mixture was concentrated to ˜15 mL, cooled to 0 ° C. and basified to pH = 3 with 2N HCl. The resulting viscous oil was diluted with 20 mL of H ₂ O and 50 mL of EtOAc to give a mixture of two clear layers. More EtOAc (about 200 mL) was added and the organic layer was separated, washed with brine, dried over MgSO ₄ , filtered and concentrated under reduced pressure. The crude was added onto a column (220 g) and purified with EtOAc in the following gradient in hexane to give (S) -6'-chloro-5-(((1R, 2R) -2-((S) -1-). Hydroxyallyl) cyclobutyl) methyl) -3 ', 4,4', 5-tetrahydro-2H, 2'H-spiro [benzo [b] [1,4] oxazepine-3,1'-naphthalene] -7-carboxylic acid was obtained as a white solid (4.22 g, 9.02 mmol, 95% yield): 0-2.5 min 0% EtOAc; 2.5-6 minutes 0% -20% EtOAc; 6-35 minutes 20% -60% EtOAc; 35-40 min 70% EtOAc.

Intermediate AA12A

S) -6'-chloro-5-(((1R, 2R) -2-((S, E) -1-hydroxyhex-2-en-1-yl) cyclobutyl) methyl) -3 ', 4,4 ', 5-tetrahydro-2H, 2'H-spiro [benzo [B] [1,4] oxazepine-3,1'-naphthalene] -7-carboxylic acid

Step 1A: (S) -Methyl 6'-chloro-5-((((1R, 2R) -2-((S, E) -1-hydroxyhex-2-en-1-yl) cyclobutyl) methyl ) -3 ', 4,4', 5-tetrahydro-2H, 2'H-spiro [benzo [B] [1,4] oxazepine-3,1'-naphthalene] -7-carboxylate

Under argon atmosphere, the dry three neck RBF filled with dry hexane (27 mL) was cooled to 0 ° C. Borane-methyl sulfide complex (3.29 mL, 34.6 mmol) and cyclohexene (7.01 mL, 69.3 mmol) were added to the solution, and the mixture was stirred at 0 ° C. for 2 hours. 1-pentin (3.41 mL, 34.6 mmol) was added to the resulting white suspension and the mixture was stirred at ambient temperature for 0.5 h. The mixture was then cooled to −78 ° C. and diethyl zinc, 1.0 M solution in hexane (32.3 mL, 32.3 mmol), was added. After addition, the mixture was warmed to 0 ° C., stirred for 3 minutes and then cooled to −78 ° C. again. This solution was named Solution A. In a separate flask, ((S) -methyl 6'-chloro-5-(((1R, 2R) -2-formylcyclobutyl) methyl) -3 ', in hexane (50.9 mL) and toluene (16.97 mL) 4,4 ', 5-tetrahydro-2H, 2'H-spiro [benzo [b] [1,4] oxazepine-3,1'-naphthalene] -7-carboxylate (intermediate AA11A of step 20A, 5.24 g, 11.54 mmol) and (2s) -3-exo- (morpholino) isobonyl (0.486 g, 2.032 mmol) were charged The mixture was stirred at ambient temperature until all solids dissolved and then 0 Under argon atmosphere, 54 mL of solution A was slowly added via syringe for 1.6 h, after stirring for 5 min at 0 ° C., the mixture was quenched with saturated NH ₄ Cl solution (70 mL) and Diluted with H ₂ O (30 mL), extracted with EtOAc (3 × 270 mL), washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated to 330 g ISCO gold column and added hexanes. Eluting with 0% to 5% EtOAc in 3.8 g of the title compound Obtained as a white solid m / z (ESI, cation) 524.1 (M + H) &lt; + &gt;.

Step 1B: (S) -tertbutyl 6'-chloro-5-(((1R, 2R) -2-((S, E) -1-hydroxyhex-2-en-1-yl) cyclobutyl) Methyl) -3 ', 4,4', 5-tetrahydro-2H, 2'H-spiro [benzo [B] [1,4] oxazepine-3,1'-naphthalene] -7-carboxylate and ( S) -tertbutyl 6'-chloro-5-(((1R, 2R) -2-((R, E) -1-hydroxyhex-2-en-1-yl) cyclobutyl) methyl) -3 ', 4,4', 5-tetrahydro-2H, 2'H-spiro [benzo [B] [1,4] oxazepine-3,1'-naphthalene] -7-carboxylate

(S) -tert-butyl 6'-chloro-5-(((1R, 2R) -2-formylcyclobutyl) methyl) -3 (of step 20B) following the procedure described for intermediate AA12A of step 1A ', 4,4', 5-tetrahydro-2H, 2'H-spiro [benzo [b] [1,4] oxazepine-3,1'-naphthalene] -7-carboxylate (3.19 g, intermediate AA11A ) Was synthesized from the title compound. The crude material was absorbed onto a plug of SiO ₂ and purified over 45 minutes using 330 g ISCO gold column eluting with 0% to 15% EtOAc in heptane (S) -tertbutyl 6'-chloro-5 -(((1R, 2R) -2-((S, E) -1-hydroxyhex-2-en-1-yl) cyclobutyl) methyl) -3 ', 4,4', 5-tetrahydro -2H, 2'H-spiro [benzo [b] [1,4] oxazepine-3,1'-naphthalene] -7-carboxylate was obtained (2.36 g). Through further elution, (S) -tert-butyl 6'-chloro-5-(((1R, 2R) -2-((R, E) -1-hydroxyhex-2-en-1-yl) cyclo Butyl) methyl) -3 ', 4,4', 5-tetrahydro-2H, 2'H-spiro [benzo [b] [1,4] oxazepine-3,1'-naphthalene] -7-carboxylate Obtained (0.45 g).

Step 2: (S) -6'-chloro-5-(((1R, 2R) -2-((S, E) -1-hydroxyhex-2-en-1-yl) cyclobutyl) methyl) -3 ', 4,4', 5-tetrahydro-2H, 2'H-spiro [benzo [B] [1,4] oxazepine-3,1'-naphthalene] -7-carboxylic acid

(S) -methyl 6'-chloro-5-(((1R, 2R) -2-((S, E) -1-hydroxyhex-2-ene in MeOH (98 mL) and THF (98 mL) -1-yl) cyclobutyl) methyl) -3 ', 4,4', 5-tetrahydro-2H, 2'H-spiro [benzo [b] [1,4] oxazepine-3,1'-naphthalene ] -7-carboxylate (from intermediate AA12A in step A; 4.6 g, 8.78 mmol) and a mixture of LiOH.H ₂ O (3.68 g, 88 mmol) (with a few drops of H ₂ O) added overnight at 50 ° C. Stirred. The solvent was removed and the residue was acidified to pH 2-3 with 1N HCl. The mixture was extracted with EtOAc (80 mL × 3) and the combined organic layers were washed with brine (10 mL), dried over anhydrous MgSO ₄ , and concentrated under reduced pressure to give (S) -6′-chloro-5-(( (1R, 2R) -2-((S, E) -1-hydroxyhex-2-en-1-yl) cyclobutyl) methyl) -3 ', 4,4', 5-tetrahydro-2H, 2'H-spiro [benzo [b] [1,4] oxazepine-3,1'-naphthalene] -7-carboxylic acid was obtained (4.25 g, 8.34 mmol, 95% yield).

Alternatively, the title compound can be synthesized as follows:

(S) -tert-butyl 6'-chloro-5-(((1R, 2R) -2-((S, E) -1-hydroxyhex-2-en-1-yl) cyclobutyl) methyl) -3 ', 4,4', 5-tetrahydro-2H, 2'H-spiro [benzo [b] [1,4] oxazepine-3,1'-naphthalene] -7-carboxylate (from step 1B Intermediate AA12A, first eluting isomer: 4.50 g, 7.95 mmol) and solid solvent mixture of LiOH.H ₂ O (1.66 g, 39.7 mmol) was added solvent dioxane / MeOH (1: 1) (159 mL) It was. The mixture was heated to 65 ° C. and stirred overnight. The mixture was then diluted with H ₂ O and acidified to 1.0 pH with 1.0 N HCl. The organic solvent was evaporated under reduced pressure and H ₂ O was added to the residue. The aqueous mixture was then extracted three times with EtOAc and the combined organic extracts were concentrated. Purify the residue using 120 g of SiO ₂ gel column eluting with 0% to 70% gradient EtOAc in hexanes to give (S) -6'-chloro-5-(((1R, 2R) -2-(( S, E) -1-hydroxyhex-2-en-1-yl) cyclobutyl) methyl) -3 ', 4,4', 5-tetrahydro-2H, 2'H-spiro [benzo [b] [1,4] oxazepine-3,1'-naphthalene] -7-carboxylic acid was obtained (3.80 g, 7.45 mmol, 94% yield).

Intermediate AA13A

(S) -6'-chloro-5-(((1R, 2R) -2-((S) -1-hydroxybut-3-en-1-yl) cyclobutyl) methyl) -3 ', 4 , 4 ', 5-tetrahydro-2H, 2'H-spiro [benzo [B] [1,4] oxazepine-3,1'-naphthalene] -7-carboxylic acid

Step 1A: (S) -Methyl 6'-chloro-5-((((1R, 2R) -2-((S) -1-hydroxybut-3-en-1-yl) cyclobutyl) methyl)- 3 ', 4,4', 5-tetrahydro-2H, 2'H-spiro [benzo [B] [1,4] oxazepine-3,1'-naphthalene] -7-carboxylate

(1R, 2R) -N-methyl-1-phenyl-1-(((1S, 5S, 10R) -10- (trimethylsilyl) -9-borabicyclo [3.3] in Et ₂ O (73 mL) under argon. .2] Oven dried 200 mL flask filled with a suspension of decan-9-yl) oxy) propan-2-amine (5.40 g, 14.54 mmol) was cooled to −78 ° C. and allyl magnesium bromide (13.22 mL, 13.22 mmol) solution was added dropwise. The mixture was warmed to ambient temperature and stirred for 1 hour. Then the solution (˜0.17 M; solution A) was cooled back down to −78 ° C.

Under argon, ((S) -methyl 6'-chloro-5-(((1R, 2R) -2-formylcyclobutyl) methyl) -3 ', 4,4', in Et ₂ O (22.03 mL), 5-tetrahydro-2H, 2'H-spiro [benzo [b] [1,4] oxazepine-3,1'-naphthalene] -7-carboxylate (intermediate AA11A from step 20A; 2.0 g, 4.41 mmol) A separate 200 mL flask filled with was cooled to -78 ° C. 40 mL of the above-mentioned Solution A was added to this solution and the resulting mixture was stirred for 40 minutes at -78 ° C. Then 4-methyl Morpholine 4-oxide (3.10 g, 26.4 mmol) was added and the mixture was allowed to warm to ambient temperature for 10 minutes methanol (10 mL) was added and the volatile organics were evaporated at ambient temperature under reduced pressure. 100 mL) was added and after stirring for 1 h at ambient temperature, the mixture was concentrated The residue was diluted with EtOAc (450 mL), 1N HCl (15 mL), Na ₂ CO ₃ solution (10 mL) And washed with brine (6 mL), anhydrous Na ₂ dried over SO ₄ and concentrated The residue was added to 220 g ISCO gold column and eluted with 0% to 5% EtOAc in hexanes to give 1.88 g of the title compound as a white solid. (ESI, cation) 496.0 (M + H) ⁺ .

Step 1B: (S) -tertbutyl 6'-chloro-5-(((1R, 2R) -2-((S) -1-hydroxybut-3-en-1-yl) cyclobutyl) methyl) -3 ', 4,4', 5-tetrahydro-2H, 2'H-spiro [benzo [B] [1,4] oxazepine-3,1'-naphthalene] -7-carboxylate

The title compound was prepared using (S) -tert-butyl 6'-chloro-5-(((1R, 2R) -2-formylcyclobutyl) methyl) -3 ', following the procedure described for intermediate AA13A of step 1A. 4,4 ', 5-tetrahydro-2H, 2'H-spiro [benzo [b] [1,4] oxazepine-3,1'-naphthalene] -7-carboxylate (intermediate AA11A, step 20B; 3.0 from g). The crude material was purified over 60 minutes using a 220 g SiO ₂ gel column eluting with 5% EtOAc in hexanes to give (S) -tert-butyl 6'-chloro-5-(((1R, 2R) -2- ((S) -1-hydroxybut-3-en-1-yl) cyclobutyl) methyl) -3 ', 4,4', 5-tetrahydro-2H, 2'H-spiro [benzo [b] [1,4] oxazepine-3,1'-naphthalene] -7-carboxylate was obtained (2.19 g).

Step 2: (S) -6′-Chloro-5-(((1R, 2R) -2-((S) -1-hydroxybut-3-en-1-yl) cyclobutyl) methyl) -3 ', 4,4', 5-tetrahydro-2H, 2'H-spiro [benzo [B] [1,4] oxazepine-3,1'-naphthalene] -7-carboxylic acid

(S) -methyl 6'-chloro-5-(((1R, 2R) -2-((S) -1-hydroxybut-3-ene-1 in MeOH (34 mL) and THF (50 mL) -Yl) cyclobutyl) methyl) -3 ', 4,4', 5-tetrahydro-2H, 2'H-spiro [benzo [b] [1,4] oxazepine-3,1'-naphthalene]- A mixture of 7-carboxylate (derived from intermediate AA13A of step 1A; 1.88 g, 3.79 mmol) and LiOH solution (1M) (34.1 mL, 34.1 mmol) was stirred at 65 ° C. for 50 minutes. After cooling to ambient temperature, the mixture is acidified to pH 2-3 with 1N HCl, extracted with EtOAc (350 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated to give 1.82 g of the title compound as a white solid. It was. m / z (ESI, cation) 482.0 (M + H) ⁺ .

Alternatively, the title compound can be synthesized as follows:

(S) -tert-butyl 6'-chloro-5-(((1R, 2R) -2-((S) -1-hydroxybut-3-en-1-yl) cyclo in DCM (3.717 mL) Butyl) methyl) -3 ', 4,4', 5-tetrahydro-2H, 2'H-spiro [benzo [b] [1,4] oxazepine-3,1'-naphthalene] -7-carboxylate To a solution of (Intermediate AA13A, Step 1B; 250 mg, 0.465 mmol) was added TFA (0.929 mL) at ambient temperature and the reaction mixture was stirred for 4 hours. The crude reaction mixture was then concentrated and the residue was dissolved in EtOAc, washed once with saturated NaHCO ₃ , dried over MgSO ₄ , filtered and concentrated to give a white foam. The crude material was used as is without further purification.

Intermediate EE11

N, N-bis (4-methoxybenzyl) amine

A solution of 4-methoxybenzaldehyde (Spectrochem; 100 g, 734.5 mmol) and 4-methoxybenzyl amide (GLR; 100 g, 734.5 mmol) in toluene (0.8 L) was used for 6 hours at 130 ° C. using a Dean-Stark apparatus. Reflux for a while. The reaction was monitored by TLC, upon completion excess solvent was removed under reduced pressure and the residue was dissolved in methanol (0.8 L). The resulting solution was cooled to 0 ° C. and sodium borohydride (36.12 g, 954.8 mmol) was added in one portion. After the addition was complete, the reaction mixture was stirred at ambient temperature for 3 hours. Methanol was removed and the residue was diluted with H ₂ O (1.0 L) and EtOAc (2.0 L). The layers were separated and the aqueous layer was extracted with EtOAc (2 × 1.0 L). The combined organic layers were washed with H ₂ O and brine and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure and the resulting crude was purified by column chromatography using SiO ₂ gel (100-200 mesh size) eluting with a gradient of 100% hexanes to 25% EtOAc in hexanes to give the title compound a colorless but Obtained as an opaque liquid (160 g, 84.6%).

Intermediate EE12

N, N-bis (4-methoxybenzyl) methanesulfonamide

Methanesulfonamide (Sigma-Aldrich, 5 g, 52.6 mmol) in 2-butanone (175 mL), p-methoxybenzyl chloride (14.98 mL, 110 mmol), anhydrous K ₂ CO ₃ ( 36.3 g, 263 mmol) and a mixture of potassium iodide (0.873 g, 5.26 mmol) were refluxed overnight (75 ° C.). The reaction was monitored by TLC and LC / MS and upon completion the mixture was cooled to ambient temperature, filtered, washed with Et ₂ O and concentrated. Crude (17.54 g, 52.3 mmol, 99% yield) was used without further purification. MS (ESI, cation) m / z: 358.1 (M + Na).

Intermediate EE13

N, N-bis (4-methoxybenzyl) ethanesulfonamide

To a solution of N, N-bis (4-methoxybenzyl) amine (intermediate EE11; 200 g, 775.19 mmol) in DCM (2.5 L) was added Et ₃ N (336.17 mL, 2325.5 mmol) and the reaction mixture was 0 Cool to C. Ethanesulfonyl chloride (95 mL, 1007.75 mmol) followed by DMAP (19.0 g, 155.03 mmol) was added dropwise. The resulting reaction mixture was stirred at ambient temperature for 30 minutes. The reaction was monitored by TLC and upon completion the mixture was diluted with H ₂ O, the layers separated and the aqueous phase extracted with DCM (3 × 1.5 L). The combined organic layers were washed with H ₂ O and brine and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure to afford crude, which was purified by column chromatography using SiO ₂ gel (100-200 mesh) eluting with 0% -12% gradient EtOAc in hexane to give the title compound as a white foamy product. Obtained as a solid (145 g, 53.4%).

Intermediate EE14

N, N-bis (4-methoxybenzyl) propanesulfonamide

To a solution of N, N-bis (4-methoxybenzyl) amine (intermediate EE11; 405 g, 1569.7 mmol) in DCM (4.0 L) was added Et ₃ N (681.0 mL, 4709.3 mmol) and the reaction mixture was 0 Cool to C. Propanesulfonyl chloride (231 mL, 2040.6 mmol) followed by DMAP (38.3 g, 313.9 mmol) was added dropwise. The resulting mixture was stirred at ambient temperature for 30 minutes. The reaction was monitored by TLC and upon completion the mixture was diluted with 2.0 L of H ₂ O, the layers separated and the aqueous phase extracted with DCM (3 × 2.0 L). The combined organic layers were washed with H ₂ O and brine and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure to afford crude, which was purified by column chromatography using SiO ₂ gel (100-200 mesh) eluting with 0-12% gradient EtOAc in hexanes to give the title compound as a white foamy solid. Obtained as (300 g, 52.44%).

Intermediate EE15

But-3-ene-1-sulfonamide

Step 1: Butyl-3-ene-1-sodium sulfonate

A mixture of 4-bromo-1-butene (LLBChem, 3.01 mL, 29.6 mmol) and sodium sulfate (4.11 g, 32.6 mmol) in H ₂ O (20 mL) was stirred at 110 ° C. overnight. The reaction was monitored by TLC and upon completion H ₂ O was removed under reduced pressure and the residue triturated with acetone. The solid obtained was filtered to give the title compound as a white solid (4.53 g), which was used as such in the next step.

Step 2: but-3-ene-1-sulfonamide

A mixture of buty-3-ene-1-sulfonate (4.50 g, 28.5 mmol) and phosphorus oxychloride (70 mL) was stirred at 135 ° C. for 7 hours. Phosphorous oxychloride was then removed under reduced pressure to give a dark colored residue containing a white solid. This residue was diluted with MeCN (20 mL) and then filtered to remove the precipitate. The filtrate was cooled to 0 ° C. and treated dropwise with ammonia solution (30% aqueous; 30 mL). After the addition was complete, the reaction was stirred at 0 ° C. for 30 minutes. The mixture was diluted with EtOAc (300 mL), washed with brine and dried over anhydrous Na ₂ SO ₄ . The solvent was removed under reduced pressure and the residue was purified by column chromatography using SiO ₂ gel (100-200 mesh; eluting with EtOAc / hexane in 1: 1 ratio) to give the title compound as a white solid (1.55 g). , Yield: 40%). MS (ESI, cation) m / z: 117.1 (M + l).

Intermediate EE16

N, N-bis (4-methoxybenzyl) but-3-ene-1-sulfonamide

But-3-en-1-sulfonamide (intermediate EE15; 1.5 g, 11.10 mmol) in 2-butanone (55.5 mL), p-methoxybenzyl chloride (3.76 mL, 27.7 mmol), anhydrous K ₂ CO ₃ (7.67 g, 55.5 mmol) and sodium iodide (0.166 g, 1.110 mmol) were refluxed (at 75 ° C.) overnight. The reaction was monitored by TLC and LC / MS and upon completion the mixture was cooled to ambient temperature, filtered and concentrated. Purification of the crude material by chromatography using SiO ₂ gel (100-200 mesh) eluting with and adsorbed on the plug of SiO ₂ gel, 0% to 30% EtOAc in hexanes to afford the title compound as a colorless oil ( 4.10 g, 10.92 mmol, 98% yield). MS (ESI, cation) m / z: 376.2 (M + l).

Intermediate EE17

(R) -pent-4-ene-2-sulfonamide

Step 1: (S) -N, N-bis (4-methoxybenzyl) pent-4-ene-2-sulfonamide and (R) -N, N-bis (4-methoxybenzyl) pent-4- N-2-sulfonamide

N, N-bis (4-methoxybenzyl) but-3-ene-1-sulfonamide (intermediate EE16; 50.0 g, 133.2 mmol) was azeotropically mixed with toluene and dried under vacuum for 1 hour. THF (890 mL) was added and the mixture was cooled to -78 ° C. Then butyllithium (2.5 M in hexane, 63.9 mL, 159.9 mmol) was added and the reaction mixture was stirred at -78 ° C for 1 hour. This anionic solution was added slowly to a solution of MeI (16.8 mL, 266.5 mmol) in THF (300 mL) and cooled to -78 ° C. The resulting reaction mixture was further stirred at −78 ° C. for 15 minutes. Upon completion of the reaction (monitored by TLC), the mixture was quenched with saturated NH ₄ Cl solution and extracted with EtOAc. The organic layer was dried over Na ₂ SO ₄ and concentrated under reduced pressure to afford crude, which was purified by column chromatography using SiO ₂ gel eluting with 5% to 10% EtOAc in hexanes to give the title compound as a semisolid compound. Obtained as a semi mixture (22.0 g). SFC (column: Chiralpak ^® AD-H, 50 X 250 mm, 5 μιη; mobile phase A: CO ₂ ; mobile phase B: ethanol; isocratic: 40% B with CO ₂ recycler on; flow rate: 200 g / Min; addition: 2.0 mL of sample (~ 100 mg) prepared as above; detection: UV @ 230 nm; cycle time: 5 min; total elution time: 10 min; instrument: Thar 350 (Lakers)) The isomers were separated to give (S) -N, N-bis (4-methoxybenzyl) pent-4-ene-2-sulfonamide as first eluting isomer (ret. Time: 2.22 min) (R)- N, N-bis (4-methoxybenzyl) pent-4-ene-2-sulfonamide was obtained as the second eluting isomer (retention time: 2.47 minutes).

Step 2: (R) -pent-4-en-2-sulfonamide

(R) -N, N-bis (4-methoxybenzyl) pent-4-ene-2-sulfonamide in DCM (2.8 mL) (Intermediate EE17, step 1; second eluting isomer; 221 mg, 0.567 mmol To the solution of) trifluoroacetic acid (1.7 mL, 22.70 mmol) was added dropwise (the clear solution turned dark very quickly). After stirring for 7 hours (30% EtOAc in hexanes; TLC indicated complete loss of starting material), the mixture was diluted with EtOAc, washed with saturated NaHCO ₃ , extracted again with EtOAc, dried over MgSO ₄ , Concentrated. The crude was purified via chromatography (12 g ISCO gold column; 0% to 40% EtOAc in hexanes) to afford (R) -pent-4-ene-2-sulfonamide (70 mg, 0.469 mmol, 83% yield).

Intermediate EE172

(S) -pent-4-ene-2-sulfonamide

This intermediate was prepared using (S) -N, N-bis (4-methoxybenzyl) pent-4-ene-2-sulfonamide (Intermediate EE17, Step 1, First) using the procedure described for intermediate EE17 in Step 2. Eluting isomers).

Intermediate EE18

(R) -hex-5-ene-3-sulfonamide

Step 1: (S) -N, N-bis (4-methoxybenzyl) hex-5-ene-3-sulfonamide and (R) -N, N-bis (4-methoxybenzyl) hex-5- En-3-sulfonamide

N, N-bis (4-methoxybenzyl) but-3-ene-1-sulfonamide (intermediate EE16; 40.0 g, 106.6 mmol) was azeotropically mixed in toluene for 2 hours under vacuum. THF (700 mL) was added under argon atmosphere and the reaction mixture was cooled to -78 ° C. Butyl lithium (2.5 M in hexane; 71.6 mL, 127.9 mmol) was added and the reaction mixture was stirred at -78 ° C for 1 h. This anionic solution was added slowly to a solution of ethyl iodide (36.44 mL, 340.1 mmol) in THF (40 mL) and cooled to -78 ° C. The resulting reaction mixture was then quenched with saturated NH ₄ Cl solution, warmed to ambient temperature and extracted with EtOAc. The organic layer was dried over Na ₂ SO ₄ and concentrated under reduced pressure to afford crude, which was purified by column chromatography using SiO ₂ gel eluting with 5% to 10% EtOAc in hexanes to give the title compound as a semisolid compound. Obtained as a semi mixture (24 g). MS (ESI, cation) m / z; 404.03 (M + 1). Sample solution of 14.4 g / 200 mL (72 mg / mL) in SFC (Sample Preparation: MeOH: DCM (3: 1); Column: Chiralpak ^® AD-H, 50 X 250 mm, 5 μιη; Mobile Phase A: CO ₂ Mobile phase B: MeOH (20 mM NH ₃ ); isocratic: 40% B; flow rate: 100 mL / min; outlet pressure: 100 bar; addition: 1.0 mL sample solution (72 mg) prepared as above; Detection: UV @ 227 nm; Cycle time: 8 minutes; Total elution time: 17 minutes; Instrument: Separation of enantiomers by Thar 350 SFC) (S) -N, N-bis (4-methoxybenzyl) hex -5-ene-2-sulfonamide is obtained as the first eluting isomer, and (R) -N, N-bis (4-methoxybenzyl) hex-5-ene-2-sulfonamide is eluted second. Obtained as isomers.

Step 2: (R) -hex-5-ene-3-sulfonamide

This intermediate was converted to (R) -N, N-bis (4-methoxybenzyl) hex-5-ene-3-sulfonamide (intermediate EE18, step 1, two) using the procedure described for intermediate EE17 in step 2. First eluting isomer).

Intermediate EE182

(S) -hex-5-ene-3-sulfonamide

This intermediate was converted to (S) -N, N-bis (4-methoxybenzyl) hex-5-ene-3-sulfonamide (intermediate EE18, step 1, first) using the procedure described for intermediate EE17 in step 2. First eluting isomer).

Intermediate EE19

N, N-bis (4-methoxybenzyl) pent-4-ene-1-sulfonamide

Step 1: Sodium pent-4-ene-1-sulfonate

5-bromo-1-pentene (Sigma Aldrich; 200 g, 1342 mmol), sodium sulfate (Strem Chemicals; 186 g, 1476) in 3 L three-necked RBF with mechanical stirrer, N ₂ gas inlet, condenser and temperature probe mmol) and H ₂ O (400 mL) were charged. The mixture was heated to reflux (set at 100 ° C. and reflux at 93-94 ° C.) for 4 hours; Aliquot NMR showed greater than 95% conversion. The mixture was concentrated and azeotropically mixed with acetone to remove H ₂ O. The crude solid was washed with acetone and filtered to give pent-4-ene-1-sulfonate (350 g, 2033 mmol).

Step 2: pent-4-ene-1-sulfonamide

Sodium pent-4-ene-1-sulfonate (100 g, 581 mmol) (approximately 150 g of crude in step 1) in a 3 L three-necked RBF with mechanical stirrer, N ₂ gas inlet, condenser and temperature probe Phosphorous oxychloride (Sigma Aldrich; 532 mL, 5808 mmol) was charged. The mixture was heated to 90 ° C. for 18 h, after which the reaction was filtered and the solids washed with MeCN. The organic solution was concentrated and POCl ₃ was removed by azeotropic mixing with MeCN to afford 85 g of pent-4-ene-1-sulfonyl chloride intermediate. This material (solution in 300 mL MeCN) was charged to a 1 L three-necked RBF equipped with a mechanical stirrer, N ₂ gas inlet, condenser and temperature probe. The reaction was cooled to 0-5 [deg.] C. and NH ₄ OH (Sigma Aldrich; 28% NH ₃ ; 404 mL, 2904 mmol) was added slowly over 30 minutes. The reaction was stirred at 0-5 [deg.] C. for 1 hour, after which EtOAc (300 mL) was added and the mixture was extracted with EtOAc and concentrated to give pent-4-ene-1-sulfonamide as a brown oil (50 g, 335 mmol, 57.7% yield).

Step 3: N, N-bis (4-methoxybenzyl) pent-4-ene-1-sulfonamide

The title compound was synthesized from pent-4-ene-1-sulfonamide (4.5 g, 30.2 mmol) following the procedure described for intermediate EE16. The crude was purified to give N, N-bis (4-methoxybenzyl) pent-4-ene-1-sulfonamide as a colorless oil (11.4 g, 29.3 mmol, 97% yield).

Intermediate EE20

(R) -hex-5-ene-2-sulfonamide

Step 1: (S) -N, N-bis (4-methoxybenzyl) hex-5-ene-2-sulfonamide and (R) -N, N-bis (4-methoxybenzyl) hex-5- N-2-sulfonamide

A solution of N, N-bis (4-methoxybenzyl) ethanesulfonamide (Intermediate EE13; 140.0 g, 400.64 mmol) in THF (1.4 L, THF purged with argon for 15 minutes before use) to -78 ° C. Cool and add butyllithium solution (2.6 M in hexane, 200.0 mL, 520.83 mmol) dropwise. The resulting solution was stirred at −78 ° C. for 10 minutes and 4-bromo-1-butene (73.2 mL, 721.15 mmol) was added over 2 minutes. After 5 minutes, the reaction was warmed to ambient temperature and stirred for 1 hour. The reaction was monitored by TLC and upon completion the mixture was quenched with saturated NH ₄ Cl solution (400 mL) and the resulting aqueous layer was extracted with EtOAc (2 × 1.0 L). The combined organic layers were washed with brine and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure to afford crude which was purified by column chromatography (SiO ₂ gel; 100-200 mesh) eluting with acetone with a gradient of 0% -4% in hexanes to give the title compound as a colorless thick oil. Obtained (racemic mixture, 80.0 g, 49.5%). MS (ESI, cation) m / z: 404.25 (M + l). SFC (sample preparation: 75 g / 1.5 L (50 mg / mL) sample solution in MeOH; column: Chiralpak® IF, 21 X 250 mm, 5 μιη; mobile phase A: CO ₂ ; mobile phase B: MeOH (0.2% DEA) Isocratic: 40% B; flow rate: 80 mL / min; outlet pressure: 100 bar; addition: 3.0 mL of sample solution (150 mg) prepared as above; detection: UV @ 225 nm; cycle time: 3.9 min; Total elution time: 6 min; Instrument: Enantiomers separated by Thar 80 SFC) to give (S) -N, N-bis (4-methoxybenzyl) hex-5-ene-2-sulfonamide Obtained as first eluting isomer and (R) -N, N-bis (4-methoxybenzyl) hex-5-ene-2-sulfonamide as second eluting isomer.

Step 2: (R) -hex-5-ene-2-sulfonamide

The title compound was prepared using (R) -N, N-bis (4-methoxybenzyl) hex-5-ene-2-sulfonamide (intermediate EE20, step 1, two) using the procedure described for intermediate EE17 in step 2. First eluting isomer).

Intermediate EE202

(S) -hex-5-ene-2-sulfonamide

The title compound was prepared using (S) -N, N-bis (4-methoxybenzyl) hex-5-ene-2-sulfonamide (intermediate EE20, step 1, first) using the procedure described for intermediate EE17 in step 2. First eluting isomer).

Intermediate EE21

(R) -hept-6-ene-3-sulfonamide

Step 1: (S) -N, N-bis (4-methoxybenzyl) hept-6-ene-3-sulfonamide and (R) -N, N-bis (4-methoxybenzyl) hept-6- En-3-sulfonamide

The title compound was synthesized from N, N-bis (4-methoxybenzyl) propanesulfonamide (intermediate EE14) using the procedure described for intermediate AA20 in step 1. Sample solution of SFC (sample preparation: 40.55 g / 200 mL (238.5 mg / mL) in MeOH; column: Chiralpak® AD-H, 50 X 150 mm, 5 μιη; mobile phase A: CO ₂ ; mobile phase B: MeOH (20 mM NH ₃ ); isocratic: 50% B; flow rate: 190 mL / min; outlet pressure: 100 bar; addition: 1.5 mL of sample solution prepared as above (357.8 mg); detection: UV @ 227 nm; Cycle time: 17.5 min; total elution time: 21 min; instrument: (S) -N, N-bis (4-methoxybenzyl) hept-6-ene-3- by separating enantiomers by Thar 350 SFC) Sulfonamide was obtained as the first eluting isomer and (R) -N, N-bis (4-methoxybenzyl) hept-6-ene-3-sulfonamide as the second eluting isomer.

Step 2: (R) -hept-6-ene-3-sulfonamide

The title compound was prepared using (R) -N, N-bis (4-methoxybenzyl) hept-6-ene-3-sulfonamide (intermediate EE21, step 1, two) using the procedure described for intermediate EE17 in step 2. First eluting isomer).

Intermediate EE212

(S) -hept-6-ene-3-sulfonamide

The title compound was prepared using (S) -N, N-bis (4-methoxybenzyl) hept-6-ene-3-sulfonamide (intermediate EE21, step 1, first) using the procedure described for intermediate EE17 in step 2. First eluting isomer).

Intermediate EE22

(2R, 3S) -3-methylhex-5-ene-2-sulfonamide

Step 1: (4S, 5S) -4,5-dimethyl-1,3,2-dioxathiolane 2,2-dioxide

(2s, 3s)-(+)-2,3-butanediol (Aldrich; 15.00 mL, 166 mmol) and CCl ₄ (120 mL) were added to 500 mL of three-necked RBF (equipped with water cooled reflux condenser and HCl trap). Added. Then SOCl ₂ (Rreagentplus; 14.57 mL, 200 mmol) was added dropwise through a syringe over 20 minutes, and the resulting mixture was heated to 98 ° C. for 45 minutes and cooled to room temperature. The reaction mixture was then cooled in an ice bath, MeCN (120 mL) and H ₂ O (150 mL) were added followed by ruthenium (III) chloride (0.035 g, 0.166 mmol). Sodium periodate (53.4 g, 250 mmol) was added slowly once over 30 minutes. The resulting biphasic brown mixture was stirred vigorously with warming to room temperature for 1.5 hours (internal temperature did not rise above room temperature). TLC (50% EtOAc in heptanes) showed complete conversion. The crude mixture was then poured into iced water and extracted twice with 300 mL of Et ₂ O. The combined organic layers were washed once with 200 mL of saturated sodium bicarbonate, once with 200 mL of brine, dried over Na ₂ SO ₄ and concentrated by rotary evaporation (4S, 5S) -4,5- Dimethyl-1,3,2-dioxathiolane 2,2-dioxide was obtained as a red oil (21.2 g, 139 mmol).

Step 2: (2S, 3S) -3-methylhex-5-en-2-ol

In a 500 mL flask, (4S, 5S) -4,5-dimethyl-1,3,2-dioxathiola 2,2-dioxide (derived from intermediate EE22 in step 1; 21.2 g, 139 mmol) and THF (220 mL ) Was added, at which time the solution was cooled to −78 ° C. and exhaust / argon backfill was performed over 3 cycles. To the solution was added a solution of dilithium tetrachlorocopper (ii), 0.1M in THF (69.7 mL, 6.97 mmol). The resulting mixture was stirred at −78 ° C. for 30 minutes, and then allylmagnesium bromide, 1.0 M solution in Et ₂ O (397 mL, 397 mmol) was slowly added over 80 minutes via cannula. The resulting mixture was stirred at 0 ° C. for 4 hours. The mixture was quenched with 200 mL of H ₂ O to warm up to room temperature, at which point volatiles were removed by rotary evaporation. 50% H ₂ SO ₄ (150 mL) was then added to the aqueous residue, the mixture was stirred for 5 minutes, then Et ₂ O (400 mL) was added and the mixture was stirred vigorously overnight at room temperature. Separating the layers; The aqueous layer was extracted with 300 mL of Et 2 O, and the combined organic layers were washed with 300 mL of saturated NaHCO ₃ , dried over Na ₂ SO ₄ , filtered and concentrated by rotary evaporation to (2S, 3S) -3-methylhex. -5-en-2-ol was obtained as a clear oil (6.7 g, 58.7 mmol).

Step 3: 2-(((2R, 3S) -3-methylhex-5-en-2-yl) thio) pyrimidine

Diethyl azo in 2000 mL dry RBF containing a stirred solution of tributylphosphine (57.7 mL, 231 mmol) in 1000 mL of degassed 0 ° C. THF (30 minutes sparging of argon plus 5 cycles of pumping / argon addition). Dicarboxylate (40 wt% solution in toluene; 103 mL, 262 mmol) was added dropwise under argon atmosphere. A solution of (2S, 3S) -3-methylhex-5-en-2-ol (derived from intermediate EE22 in step 2; 17.6 g, 154 mmol; dried with Na ₂ SO ₄ ) as a solution in 50 mL of THF To the solution of phosphine / diethyl azodicarboxylate complex was added dropwise via syringe-filter (0.45 um). The resulting ROH / diethyl azodicarboxylate / tri-n-butylphosphine mixture was aged at 0 ° C. for 15 minutes (solution turned bright orange), at which time pyrimidine-2-thiol (49.3 g, 439 mmol) was added gradually to the top of the reaction vessel under positive pressure argon (as a solid). The reaction was stirred at 0 ° C. for 1 hour and then at room temperature for 15 hours (reaction was not completed in 12 hours by LC / MS). The crude reaction was then filtered to remove excess pyrimidine-2-thiol, diluted with 1000 mL of EtOAc, extracted twice with 500 mL of 1 NK ₂ CO ₃ and once with 500 mL of brine. . The aqueous layer was extracted again with 300 mL of EtOAc and the combined organic layers were dried over Na ₂ SO ₄ . The organic solution was then filtered, the solvent was removed by rotary evaporation, and the crude was filtered to remove (E) -diethyl diagen-1,2-dicarboxylate produced in the reaction. The filtrate (125 g) was passed through a SiO ₂ plug (500 g SiO ₂ , eluted with 2 L of DCM) to yield 75 g of crude product after solvent removal. The crude product was purified again using Combiflash® ⁽ 125 g Gold SiO ₂ column) eluting with 10% EtOAc in heptanes to give 2-(((2R, 3S) -3-methylhex-5-en-2-yl) Thio) pyrimidine was obtained as a light yellow oil (20.37 g, 98 mmol).

Step 4: 2-(((2R, 3S) -3-methylhex-5-en-2-yl) sulfonyl) pyrimidine

In 500 mL three-necked RBF with reflux condenser, phenylphosphonic acid (3.95 g, 24.96 mmol), tungsten sodium oxide dihydrate (8.23 g, 24.96 mmol), tetrabutylammonium sulfate (50 wt% solution in H ₂ O, 28.7 mL, 24.96 mmol), catalytic amount of hydrogen peroxide (30% in H ₂ O, 12.75 mL, 125 mmol), toluene (200 mL) and 2-(((2R, 3S) -3-methylhex-5-ene- 2-yl) thio) pyrimidine (derived from intermediate EE22 of step 3; 52 g, 250 mmol) was added. The reaction was stirred at 45 ° C. for 5 minutes, at which time 30% hydrogen peroxide (58.6 mL, 574 mmol) in H ₂ O was added once (10 mL at a time). Five minutes after the first addition of hydrogen peroxide, exotherm (65 ° C.) was observed, the addition was stopped and the reaction removed from the oil bath and the flask was placed in a water bath until the temperature stabilized. The flask was removed from the water bath and hydrogen peroxide was continuously added once (at approximately 40 minutes) at a rate where the internal temperature remained at 45 ° C. to 55 ° C. An ice bath was used when the temperature exceeded 60 ° C. and an oil bath was used when the temperature dropped below 45 ° C. The reaction was then stirred at 45 ° C. for 1 hour. The reaction was diluted with 1400 mL of EtOAc and extracted twice with 500 mL of H ₂ O and once with 500 mL of brine. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated, and the crude was purified using Combiflash ^{® (} 330 g of Gold SiO ₂ column / 30 g of crude) eluting with 0% to 50% EtOAc in heptane. 2-(((2R, 3S) -3-methylhex-5-en-2-yl) sulfonyl) pyrimidine was obtained as a yellow oil (55.7 g, 232 mmol).

Step 5: (2R, 3S) -3-Methylhex-5-ene-2-sulfinate

Room temperature of 2-(((2R, 3S) -3-methylhex-5-en-2-yl) sulfonyl) pyrimidine (from intermediate EE22 of step 4; 52 g, 216 mmol) in MeOH (400 mL) To the solution was added sodium methoxide solution (51.0 mL, 223 mmol) over 70 minutes. Sodium methoxide was added once and the internal temperature was monitored and the addition was slowed or the reaction cooled in a water bath so that the internal temperature never exceeded 30 ° C. The mixture is concentrated by rotary evaporation, the waxy solid is ground with MTBE (200 mL of MTBE is added and stirred for 1 hour with a spatula to break the clump), filtered (filtration cake) Above with N ₂ stream), washed with 100 mL of cold MTBE to give (2R, 3S) -3-methylhex-5-ene-2-sulfinate (46 g, 250 mmol) as an off-white solid.

Step 6: (2R, 3S) -3-methylhex-5-ene-2-sulfonamide

In 1000 mL of three-necked RBF (2R, 3S) -3-methylhex-5-ene-2-sulfinate (from intermediate EE22 in step 5; 46 g, 225 mmol), 500 mL of H ₂ O and KOAc (44.1 g, 449 mmol) was added at room temperature. The flask was placed in an oil bath at 45 ° C. and hydroxylamine-O-sulfonic acid (21.09 g, 187 mmol) was added once over 90 minutes. The internal temperature of the reaction was monitored and (if necessary) the reaction was taken out of the oil bath to adjust the exotherm (Tmax = 55 ° C). The reaction was monitored every 10 minutes by LC / MS and the reaction was complete after addition of 0.83 equivalents of hydroxylamine-O-sulfonic acid. The mixture was then cooled to room temperature and extracted with 1000 mL of EtOAc. The organic phase is extracted three times with 500 mL of 1 N HCl, twice with 300 mL of saturated sodium bicarbonate, once with 200 mL of brine, dried over Na ₂ SO ₄ , filtered and concentrated by rotary evaporation. (2R, 3S) -3-methylhex-5-ene-2-sulfonamide was obtained as a white solid (32 g, 181 mmol).

Intermediate 1

(1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-7 ', 11', 12'-dimethyl-3,4- Dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0 ^{3,6 19,24} ] pentacosa [8,16,18,24] tetraene] -15'-on 13 ', 13'-dioxide

Step 1: (S) -6'-chloro-5-(((1R, 2R) -2-((S) -1-hydroxyallyl) cyclobutyl) methyl) -N-(((2R, 3S) -3-methylhex-5-en-2-yl) sulfonyl) -3 ', 4,4', 5-tetrahydro-2H, 2'H-spiro [benzo [B] [1,4] oxazepine -3,1'-naphthalene] -7-carboxamide

(S) -6'-Chloro-5-((((1R, 2R) -2-((S) -1-hydroxyallyl) cyclobutyl) methyl) -3 ', 4,4 in DCM (411 mL) ', 5-tetrahydro-2H, 2'H-spiro [benzo [b] [1,4] oxazepine-3,1'-naphthalene] -7-carboxylic acid (intermediate AA11A; 7.7 g, 16.45 mmol) and ( DMAP (3.42 g, 28.0 mmol) was added to a solution of 2R, 3S) -3-methylhex-5-ene-2-sulfonamide (intermediate EE22; 5.83 g, 32.9 mmol) and cooled to 0 ° C. Then, EDC hydrochloride (6.31 g, 32.9 mmol) was slowly added once. The mixture was stirred while allowing to reach ambient temperature overnight. The mixture was washed with 1N HCl and brine and the aqueous layer was extracted again with EtOAc. The combined organics were dried over MgSO ₄ , filtered and concentrated. The yellow oil residue was added onto a 220 ISCO gold column and purified by eluting with 0% to 20% EtOAc in 0.3 heptanes containing 0.3% AcOH in (S) -6'-chloro-5-(((1R, 2R) -2-((S) -1-hydroxyallyl) cyclobutyl) methyl) -N-(((2R, 3S) -3-methylhex-5-en-2-yl) sulfonyl) -3 ', 4,4', 5-tetrahydro-2H, 2'H-spiro [benzo [b] [1,4] oxazepine-3,1'-naphthalene] -7-carboxamide was obtained (7.89 g, 12.58 mmol, 76% yield).

Step 2: (1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-7 ', 11', 12'-dimethyl-3 , 4-Dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazettracyclo [14.7.2.0 ^3,6 .0 ^19,24 ] Pentacosa [8,16,18,24] tetraene] -15'-on 13 ', 13'-dioxide

20 L reactor wrapped with argon was charged with 14 L 1,2-DCE. (S) -6'-Chloro-5-(((1R, 2R) -2-((S) -1-hydroxyallyl) cyclobutyl) methyl) -N-(((2R, 3S) -3- Methylhex-5-en-2-yl) sulfonyl) -3 ', 4,4', 5-tetrahydro-2H, 2'H-spiro [benzo [b] [1,4] oxazepine-3, 1'-naphthalene] -7-carboxamide (18.75 g, 29.9 mmol) was added as a solution in 400 mL of 1,2-DCE followed by 400 mL rinse. The reactor was sealed and purged with argon. Hoveyda-Grubbs II (1.873 g, 2.99 mmol) was added as a solution in 150 mL of 1,2-DCE followed by 50 mL rinse. The argon sweep of the headspace heated the reactor to 60 ° C. over 1 hour and maintained the temperature for 9 hours. The reaction was quenched by addition of 2- (2- (vinyloxy) ethoxy) ethanol (1.501 g, 11.36 mmol), cooled to ambient temperature and concentrated to a volume of approximately 200 mL by rotary evaporation. The reaction was transferred to 1 L of RBF and diluted to 500 mL volume using 1,2-DCE. The reaction was treated with 52 g of Silicycle Si-thiol (SiliCycle Inc., Quebec, Canada; Catalog No. R51030B) with stirring at 40 ° C. for 9 hours, filtered and rinsed with 2 × 65 mL DCM. . The solution was passed through Whatman GF / F filter cups (GE Healthcare Bio-Sciences, Pittsburgh, Pa.) To obtain a clear yellow solution. The reaction was concentrated to give 27.4 g of crude product mass. The residue was slurried in 250 mL of IPAc and evaporated three times until dry. The reaction was suspended in 270 mL of IPAc, heated to dissolve, cooled to ambient temperature and stirred for 18 hours. The solids were filtered off and washed with 65 mL of IPAc. The solids were air dried for 30 minutes and then placed under high vacuum for 3 hours to give 12.56 g of (1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7 ' -Hydroxy-11 ', 12'-dimethyl-3,4-dihydro-2h, 15'h-spiro [naphthalene-1,22'-[20] oxa [13] thia [1,14] diaza Tetracyclo [14.7.3,6,0] pentacosa [8,16,18,24] tetraen] -15'-one 13 ', 13'-dioxide was obtained, which was 91.7 wt%. ¹ H NMR (500 MHz, CD ₂ Cl ₂ ) δ 8.06 (s, 1 H), 7.71 (d, J = 8.56 Hz, 1 H), 7.17 (dd, J = 8.44, 2.32 Hz, 1 H), 7.09 (d, J = 2.20 Hz, 1 H), 6.91 (s, 3 H), 5.81 (ddd, J = 14.92, 7.82, 4.16 Hz, 1 H), 5.71 (dd, J = 15.41, 8.31 Hz, 1 H ), 4.16-4.26 (m, 2H), 3.83 (d, J = 14.43 Hz, 1 H), 3.69 (d, J = 14.43 Hz, 1 H), 3.25 (d, J = 14.43 Hz, 1 H) , 3.04 (dd, J = 15.28, 9.66 Hz, 1 H), 2.68-2.84 (m, 2 H), 2.41 (app qd, J = 9.80, 3.70 Hz, 1 H), 2.25-2.34 (m, 1 H ), 1.93-2.00 (m, 5H), 1.74-2.11 (m, 9H), 1.62-1.73 (m, 1H), 1.43 (d, J = 7.09 Hz, 3H) 1.35-1.42 (m, 1 H) 1.03 (d, J = 6.60 Hz, 3 H). MS (ESI, cation) m / z 599.2 (M + H) ⁺ .

Intermediate 2

(1S, 3'R, 6'R, 7'S, 11'R, 12'R) -6-chloro-7'-hydroxy-11 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.3,6,19,24] pentacosa [16,18,24] Triene] -15'-on 13 ', 13'-dioxide

(1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-11 ', 12'-dimethyl-3 in EtOAc (1.536 mL) , 4-dihydro-2h, 15'h-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazettracyclo [14.7.3,6,19,24] penta A mixture of cosa [8,16,18,24] tetraen] -15'-one 13 ', 13'-dioxide (intermediate 1, 7.5 mg, 0.013 mmol) and platinum (IV) oxide (2.84 mg, 0.013 mmol) Was stirred at ambient temperature under H ₂ atmosphere (balloon) for 45 minutes. The reaction mixture was then filtered through a syringe filter. The crude material was purified by chromatography over a Redi-Sep ^® prefilled SiO ₂ gel column (4 g) eluting with 15% to 50% EtOAc in heptane (containing 0.3% AcOH) to afford the title product. ¹ H NMR (400 MHz, CD ₂ Cl ₂ ) δ 8.24 (br. S., 1H), 7.71 (d, J = 8.4 Hz, 1H), 7.17 (dd, J = 2.3, 8.4 Hz, 1H), 7.09 ( d, J = 2.2 Hz, 1H), 7.06 (d, J = 1.8 Hz, 1H), 6.99 (dd, J = 2.0, 8.0 Hz, 1H), 6.93 (d, J = 8.2 Hz, 1H), 4.10 ( s, 2H), 4.05 (ddd, J = 1.2, 7.2, 14.3 Hz, 1H), 3.82 (d, J = 15.3 Hz, 1H), 3.74-3.69 (br. S., 1H), 3.68 (d, J = 14.3 Hz, 1H), 3.23 (d, J = 14.3 Hz, 1H), 3.06 (dd, J = 7.3, 15.4 Hz, 1H), 2.84-2.68 (m, 2H), 2.38 (d, J = 3.5 Hz , 2H), 2.08-1.96 (m, 3H), 1.96-1.88 (m, 1H), 1.88-1.75 (m, 2H), 1.74-1.56 (m, 4H), 1.47 (d, J = 12.1 Hz, 2H ), 1.40 (d, J = 7.2 Hz, 3H), 1.32-1.26 (m, 2H), 1.23-1.15 (m, 2H), 1.00 (d, J = 6.8 Hz, 3H). MS (ESI, cation) m / z 601.2 (M + H) ⁺ .

Intermediate 3

(1S, 3'R, 6'R, 8'E, 12'S) -6-chloro-12'-methyl-3,4-dihydro-2H, 7'H, 15'H-spiro [naphthalene-1, 22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0 ^{3,6 19,24} ] pentacosa [8,16,18,24] tetraen] -7' , 15'-dione 13 ', 13'-dioxide

Allyl alcohol (310 mg, 0.520 mmol, intermediate 1) was dissolved in DCM (6.0 mL) and cooled to 0 ° C. Then des-Martin periodinan (270 mg, 0.63 mmol) was added and the reaction mixture was stirred for 1.5 h. 90 mg of Dess-Martin reagent was further added at 0 ° C. and further stirred at 0 ° C. for 45 minutes. The reaction was quenched with 20 mL of 1M Na ₂ S ₂ O ₃ and warmed to room temperature. The mixture was extracted three times with DCM (40 mL). The combined organic layers were washed with water (1 x 30 mL) and then dried over magnesium sulfate. The crude product was purified by medium pressure chromatography (silica; 10% to 100% EtOAc in hexanes containing 0.3% HOAc) (1S, 3'R, 6'R, 8'E, 12'S) -6-chloro-12 '-Methyl-3,4-dihydro-2H, 7'H, 15'H-spiro [naphthalene-1,22'-[20] oxa [13] thia [1,14] diazatetracyclo [14.7. 2.0 ^3,6 .0 ^19,24 ] pentacosa [8,16,18,24] tetraene] -7 ', 15'-dione 13', 13'-dioxide was obtained (230 mg, 0.385 mmol, 74.0% yield). ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.32-9.05 (m, 1H), 7.69-7.90 (m, 1H), 7.35-7.48 (m, 1H), 7.17-7.27 (m, 1H), 7.06-7.16 (m, 1H), 6.81-6.99 (m, 2H), 6.59-6.72 (m, 1H), 5.93 (d, J = 15.65 Hz, 1H), 4.01-4.24 (m, 3H), 3.74-3.97 (m , 3H), 3.26 (d, J = 14.48 Hz, 1H), 2.92-3.16 (m, 2H), 2.69-2.89 (m, 2H), 1.70-2.26 (m, 9H), 1.48-1.56 (m, 3H ), 1.35-1.46 (m, 1H), 1.29 (t, J = 7.14 Hz, 1H), 1.07-1.19 (m, 3H). m / z (ESI, cation) 596.7 (M + H) ⁺ .

Intermediate 4

(1S, 3'R, 6'R, 11'S, 12'R) -6-chloro-11 ', 12'-dimethyl-3,4-dihydro-2H, 7'H, 15'H-spiro [ Naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0 ^{3,6 19,24} ] pentacosa [16,18,24] triene]- 7 ', 15'-dione 13', 13'-dioxide

(1S, 3'R, 6'R, 7'S, 8'E, 11'S, 12'R) -6-chloro-7'-hydroxy-11 ', 12'-dimethyl-3 in EtOAc (50 mL) , 4-dihydro-2h, 15'h-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.03,6.019,24] pentacosa [ 8,16,18,24] tetraene] -15'-on 13 ', 13'-dioxide (1.20 g, 2.02 mmol, intermediate 1) was added platinum (IV) oxide (92.0 g, 0.40 mmol) The reaction was fitted with a H ₂ balloon and vigorously stirred for 15 hours. The reaction mixture was then filtered through Celite and concentrated. The concentrate was dissolved in dichloromethane (20 mL) and then des-martin periodinan (0.95 g, 2.2 mmol) was added four times at 0 ° C. over 5 minutes. After the reaction was stirred at 0 ° C. for 15 minutes, the reaction was quenched with 0 ° C. 1N sodium thiosulfate solution (10 mL) and stirred vigorously at room temperature for 30 minutes. Then the reaction mixture was extracted (EtOAc). The separated organic layer was washed (with brine), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0% to 25% EtOAc in hexanes containing 0.1% HOAc) (1S, 3'R, 6'R, 11'S, 12'R) -6-chloro-11 ' , 12'-dimethyl-3,4-dihydro-2H, 7'H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13] thia [1,14] diazatetracyclo [14.7.2.0 ^3,6 .0 ^19,24 ] ^Pentacosa [16,18,24] triene] -7 ', 15'-dione 13', 13'-dioxide was obtained as a solid (0.85 g, 70% yield). MS (ESI, cation) m / z 599.2 (M + H) ⁺ .

Biological analysis

Cell-Free Mcl-1: Bim Affinity Assay (Mcl-1 HTRF)

Inhibition of Mcl-1 / Bim interactions was measured using time-resolved fluorescence resonance energy transfer (TR-FRET) analysis. Recombinant human Mcl-1 (residues 171-327, C-terminal Mcl-1 tagged with 6xHis) was generated by Amgen Inc (Thousand Oaks, CA). Biotinylated peptides derived from human Bim (residues 51-76) were purchased from CPC Scientific, San Jose, CA. TF-FRET analysis was performed in a total volume of 40 μL in 384-well white OptiPlate ^™ (PerkinElmer, Waltham, Mass.). The reaction mixture was 0.1 nM Mcl-1 (171-327); 0.05 nM Biotin-Bim (51-76); 0.05 nM LANCE ^® Eu-W1024 anti-6xHis from PerkinElmer; 0.072 nM Streptavidin-Xlent (Cisbio, Bedford, Mass.); And 20 mM Hepes, pH 7.5, 150 mM NaCl, 0.016 mM Brij ^® 35, and 1 mM dithiothreitol, which were serially diluted in binding buffer. The test compound was added to the Mcl-1 (171-327) and biotin -Bim After pre-incubation for 60 minutes with (51-76), the detection mixture (LANCE ^® Eu-W1024 anti -6xHis and Streptavidin-Xlent). The reaction plate was further incubated overnight and then read on an Envision ^® multimode reader (PerkinElmer). Fluorescence signals were measured at 620 nm (40-nm bandwidth) and 665 nm (7.5-nm bandwidth) with 60 μs delay after excitation at 320 nm (75-nm bandwidth). Signal ratios at 665/620 nm corresponded to the Mcl-1 / Bim interactions, which were used in all data analysis. IC ₅₀ values of test compounds were determined from duplicate data by analyzing a competition curve using a four-parameter S-shaped model in GraphPad Prism (GraphPad Software, San Diego, Calif.) Or Genedata Screener ^{® (} Genedata, Basel, Switzerland). .

Cell Viability Assay (OPM-2 10 FBS)

OPM-2, a human multiple myeloma cell line, was cultured in complete growth medium containing RPMI 1640 and 10% fetal bovine serum (FBS). Cells were seeded in 384-well plates at a density of 3000 cells per well in complete growth medium containing 10% FBS and incubated for 16 hours with test compounds serially diluted in a 37 ° C. incubator under 5% CO ₂ . Cell viability was tested using the CellTiter-Glo ^® assay (Promega, Madison, WI) according to the manufacturer's recommendations. Luminescence was added to the detection reagent is determined using the EnVision ^® Multi cover plate reader (Multilabel plate reader) after 25 minutes. Logistical 4-parameter fit models were then used in GraphPad Prism (GraphPad Software, San Diego, Calif.) Or Genedata Screener ^{® (} Genedata, Basel, Switzerland) to calculate IC ₅₀ values with Xlfit. .

The results for the compounds tested in these biological assays are shown in Tables 4 and 5 below.

Example number Mcl-1 HTRF IC ₅₀
(μM) OPM-2 10% FBS IC ₅₀ IP (μM) One 0.000086 0.085 2 0.000109 0.076 3 0.000094 0.060 4 0.000116 0.094 5 0.000098 0.040 6 0.000079 0.076 7 0.000058 0.025 8 0.000053 0.025 9 0.000078 0.050 10 0.000103 0.075 11 0.000098 0.051 12 0.000072 0.022 13 0.000094 0.063 14 0.000080 0.059 15 0.000119 0.071 16 0.000065 0.053 17 0.000073 0.034 18 0.000060 0.022 19 0.000125 0.047 20 0.000082 0.022 21 0.000156 0.047 22 0.000669 2.230 23 0.000071 0.024 24 0.000086 0.035 25 0.000113 0.041 26 0.000079 0.032 27 0.000095 0.029 28 0.000082 0.111 29 0.000249 0.186 30 0.000110 0.166 31 0.000184 0.216 32 0.000128 0.147 33 0.008250 5.570 34 0.000495 0.379 35 0.000218 0.235 36 0.000554 0.518 37 0.000615 0.643 38 0.000342 0.489 39 0.000377 0.389 40 0.000444 0.571 41 0.000642 0.810 42 0.000170 0.149 43 0.001640 0.888 44 0.000288 1.360 45 0.000245 0.891 46 0.000107 0.167 47 0.000131 0.285 48 0.000140 0.407 49 0.000087 0.185 50 0.000736 1.530 51 0.000072 0.099 52 0.000522 0.330 53 0.000336 0.290 54 0.000173 0.129 55 0.000162 0.080 56 0.000083 0.079 57 0.000258 0.090 58 0.000719 0.095 59 0.000116 0.048 60 0.000287 0.129 61 0.000075 0.124 62 0.000115 0.110 63 0.000173 0.582 64 0.000126 0.201 65 0.000451 1.500 66 0.000246 0.318 67 0.000197 0.149 68 0.000397 1.520 69 0.003830 1.480 70 0.001326 3.140 71 0.000371 1.140 72 0.000800 0.185 73 0.000609 0.129 74 0.002290 3.360 75 0.002047 1.610 76 0.003815 0.670 77 0.001217 0.415 78 0.000573 0.175 79 0.001800 0.245 80 0.001550 0.205 81 0.000140 0.112 82 0.000394 0.520 83 0.000223 0.245 84 0.000106 0.061 85 0.000491 0.274 86 0.00390 7.95 87 0.000127 0.141 88 0.000139 0.074 89 0.003750 8.210 90 0.004660 8.980 91 0.000203 0.559 92 0.000143 0.199 93 0.000530 0.924 94 0.000191 0.140 95 0.000189 0.338 96 0.000114 0.111 97 0.000299 0.228 98 0.000373 0.183 99 0.000243 0.310 100 0.000188 1.650 101 0.000196 0.263 102 0.000182 0.416 103 0.000452 0.737 104 0.001119 0.782 105 0.000423 0.655 106 0.000299 0.308 107 0.001138 0.872 108 0.000198 0.116 109 0.001042 0.916 110 0.000505 1.720 111 0.000362 0.301 112 0.000617 0.654 113 0.001190 1.330 114 0.000104 0.068 115 0.001370 0.686 116 0.000244 0.387 117 0.000352 0.358 118 0.000215 0.558 119 0.000465 0.694 120 0.000263 0.304 121 0.000084 0.120 122 0.000087 0.138 123 0.000205 0.228 124 0.000646 0.598 125 0.006100 1.475 126 0.000627 0.900 127 0.000395 6.120 128 0.000256 19.600 129 0.001694 2.630 130 0.000920 1.580 131 0.000249 0.482 132 0.000613 0.263 133 0.000189 0.136 134 0.004640 3.000 135 0.008175 > 33.3 136 0.004700 1.020 137 0.004740 1.150 138 0.026700 > 33.3 139 0.032017 > 33.3 140 0.000098 0.125 141 0.000152 0.367 142 0.000157 0.174 143 0.000432 0.219 144 0.000271 0.163 145 0.000124 0.113 146 0.000337 0.150 147 0.000376 0.157 148 0.001200 1.610 149 0.000128 0.119 150 0.000193 0.245 151 0.000843 0.462 152 0.000092 0.110 153 0.000960 10.800 154 0.000197 0.554 155 0.000228 0.378 156 0.000096 0.062 157 0.000126 0.121 158 0.000092 0.018 159 0.000096 0.079 160 0.000221 0.148 161 0.000094 0.113 162 0.000072 0.055 163 0.000179 0.130 164 0.000047 0.031 165 0.000190 0.182 166 0.000107 0.050 167 0.000086 0.052 168 0.000138 0.052 169 0.000140 0.074 170 0.000131 0.075 171 0.000074 0.122 172 0.000137 0.055 173 0.000173 0.323 174 0.000322 0.639 175 0.000069 0.064 176 0.000118 0.149 177 0.000153 0.615 178 0.000177 0.071 179 0.000072 0.036 180 0.000106 0.081 181 0.000324 0.074 182 0.000171 0.088 184 0.000068 0.017 185 0.000170 1.060 186 0.000255 0.431 187 0.000066 0.043 188 0.000084 0.038 189 0.000084 0.033 190 0.000087 0.053 191 0.000096 0.042 192 0.000078 0.065 193 0.000096 0.023 194 0.000148 0.054 195 0.000214 0.065 196 0.000470 0.304 197 0.000364 0.129 198 0.000181 1.314 199 0.000119 0.208 200 0.000315 0.583 201 0.000119 0.244 202 0.000058 0.142 203 0.000113 0.112 204 0.000230 0.319 205 0.000263 0.437 206 0.000223 6.300 207 0.000137 0.395 208 0.000099 0.368 209 0.000552 0.437 210 0.000138 0.185 211 0.000147 0.156 212 0.000122 0.307 213 0.000239 0.400 214 0.000071 0.084 215 0.000149 0.107 216 0.000490 0.183 217 - 0.192 218 0.000142 0.092 219 0.000073 0.047 220 0.000052 0.042 221 0.000069 0.120 222 0.000080 0.118 223 0.000251 0.258 224 0.000127 0.157 225 0.000087 0.280 226 0.000057 0.049 227 0.000207 0.131 228 0.000200 0.0931 229 0.000619 0.096 230 0.000051 0.070 231 0.000061 0.098 232 0.000141 0.200 233 0.000516 0.202 234 0.000163 0.071 235 0.000180 0.120 236 0.000097 0.087 237 0.000130 0.064 238 0.000176 0.076 239 0.000146 0.148 240 0.000128 0.141 241 0.000150 0.137 242 0.000249 0.791 243 0.000078 0.106 244 0.001654 0.638 245 0.000120 0.058 246 0.000099 0.138 247 0.000129 0.107 248 0.000222 0.518 249 0.000063 0.114 250 0.000071 0.047 251 0.002260 3.870 252 0.001375 1.800 253 0.000804 0.887 254 0.001200 0.544 255 0.001740 1.480 256 0.000433 1.640 257 0.000403 0.981 258 0.000069 0.095 259 0.000230 0.254 260 0.000083 0.103 261 0.000153 0.146 262 0.000093 0.089 263 0.000147 0.124 264 0.000396 0.771 265 0.000423 0.578 266 0.000282 0.723 267 0.000297 0.250 268 0.000065 0.072 269 0.000104 0.086 270 0.000035 4.860 271 0.000031 0.359 272 0.000144 0.137 273 0.000494 0.501 274 0.000285 0.232 275 0.000176 0.082 276 0.000096 0.110 277 0.000058 0.057 278 0.000039 0.574 279 0.000084 0.453 280 0.000052 0.073 281 0.000181 0.152 282 0.000118 0.486 283 0.000354 0.839 284 0.000288 0.230 285 0.000107 0.062 286 0.000155 0.050 287 0.000137 0.050 288 0.000484 0.652 289 0.000214 0.131 290 0.000215 0.149 291 0.000083 0.104 292 0.000356 0.399 293 0.000242 0.207 294 0.000660 0.687 295 0.000321 0.104 296 0.000211 1.310 297 0.000128 0.066 298 0.000279 0.262 299 0.000367 0.456 300 0.000165 0.284 301 0.000196 0.141 302 0.000107 0.084 303 0.000150 0.101 304 0.000226 0.239 305 0.000330 0.327 306 0.000282 0.246 307 0.000087 0.041 308 0.000111 0.070 309 0.000215 0.064 310 0.000117 0.517 311 0.000324 0.362 312 0.000576 0.408 313 0.000225 0.131 314 0.000118 0.126 315 0.000122 0.124 316 0.000166 0.047 317 0.000186 0.088 318 0.000138 0.077 319 0.000081 0.087 320 0.000524 0.302 321 0.000145 0.092 322 0.000145 0.087 323 0.000166 0.169 324 0.000136 0.057 325 0.000180 0.192 326 0.000307 0.488 327 0.000214 0.174 328 0.000087 0.048 329 0.000137 0.243 330 0.000425 0.278 331 0.000184 0.230 332 0.000096 0.089 333 0.000088 0.082 334 0.000186 0.159 335 0.000148 0.133 336 0.000085 0.051 337 0.000090 0.059 338 0.000100 0.057 339 0.000117 0.153 340 0.000128 0.060 341 0.000052 0.042 342 0.000089 0.104 343 0.000093 0.094 344 0.000116 0.057 345 0.000803 1.040 346 0.000062 0.066 347 0.000392 0.871 348 0.002625 5.360 349 0.001610 7.790 350 0.012333 > 33.3 351 0.000121 0.196 352 0.000111 0.162 353 0.000135 0.186 354 0.000214 0.450 355 0.000172 0.272 356 0.000110 0.367 357 0.000067 0.118 358 0.000066 0.144 359 0.002080 > 33.3 360 0.001067 2.410 361 0.000101 0.028 362 0.000061 0.058 363 0.000080 0.101 364 0.192500 > 33.3 365 0.000104 0.032 366 0.000248 0.133 367 0.000201 0.273 368 0.000069 0.068 369 - 0.071 370 - 0.369 371 0.000101 0.043 372 0.000175 0.085 373 0.000069 0.060 374 0.000095 0.041 375 0.000102 0.042 376 0.000152 0.064 377 0.000130 0.055 378 0.001187 1.415 379 0.000220 0.235 380 0.000712 0.338 381 0.000157 0.262 382 0.000130 0.106 383 0.000194 0.182 384 0.000324 0.266 385 0.000762 0.717 386 0.000273 0.211 387 0.000291 0.272 388 0.000069 0.194 389 0.000218 0.278 390 0.000095 0.068 391 0.001120 1.710 392 0.000443 4.610 393 0.000079 1.590 394 0.000533 0.461 395 0.000302 1.960 396 0.000084 1.020 397 0.000532 1.820 398 0.001007 5.585 399 0.000401 2.100 400 0.001100 2.872 401 0.002380 2.170 402 0.001399 0.745 403 0.000472 0.215 404 0.000565 0.319 405 0.000057 0.018 406 0.000304 0.329 407 0.000751 0.567 408 0.000225 4.610 409 0.000214 0.140 410 0.000327 0.247 411 0.000930 0.796 412 0.001410 0.749 413 0.000257 0.145 414 0.000154 1.840 415 0.000294 4.020 416 0.000423 6.910 417 0.001750 6.320 418 0.000662 0.515 419 0.003310 2.140 420 0.000176 0.080 421 0.001175 0.596 422 0.000289 0.405 423 0.000269 0.626 424 - 2.240 425 0.000281 0.086 426 0.001315 2.170 427 0.000208 0.141 428 0.000154 0.316 429 0.000214 0.174 430 0.002475 1.310 431 0.000555 0.206 432 0.000229 0.302 433 0.001186 1.670 434 0.000585 0.913 435 0.000380 0.152 436 0.000156 3.200 437 0.000201 0.080 438 0.000308 0.230 439 0.000427 0.505 440 0.000140 0.038 441 0.000459 0.443 442 0.000221 0.286 443 0.001255 0.555 444 0.000128 0.251 445 0.000282 0.161 446 0.000776 0.446 447 0.000119 0.069 448 0.000315 0.581 449 0.000449 0.290 450 0.000112 0.791 451 0.001006 1.810 452 0.003375 17.200 453 0.000451 0.611 454 0.000174 0.213 455 0.000104 0.110 456 0.001045 0.908 457 0.001468 2.610 458 0.000848 0.439 459 0.000225 0.267 460 0.000147 0.161 461 0.000111 0.218 462 0.000261 0.198 463 0.000439 0.322 464 0.000387 0.426 465 0.000581 0.536 466 0.000900 0.446 467 0.000223 0.173 468 0.001075 1.210 469 0.000075 0.295 470 0.000156 0.122 471 0.000321 0.943 472 0.000167 0.068 473 0.000112 0.025 474 0.000088 0.042 475 0.000411 0.350 476 0.000223 0.173 477 0.000240 0.403 478 0.000423 0.197 479 0.000315 4.980 480 0.000067 0.113 481 0.000212 1.110 482 0.000180 0.590 483 0.000244 0.260 484 0.000075 0.162 485 0.000292 1.210 486 0.000081 0.269 487 0.000221 1.500 488 0.000076 0.183 489 0.000035 0.046 490 0.000288 1.860 491 0.000096 0.453 492 0.000295 0.516 493 0.000109 0.170 494 0.000276 1.480 495 0.000075 0.082 496 0.000105 0.207 497 0.000469 1.210 498 0.000120 0.143 499 0.000355 0.110 500 0.000147 0.078 501 0.000672 5.030 502 0.000069 0.191 503 0.000331 0.200 504 0.000159 0.087 506 0.003800 7.430 507 0.013700 > 33.3 508 0.000248 1.130 509 0.000155 0.744 510 0.000258 1.520 511 0.000493 1.380 512 0.000170 0.363 513 0.000235 0.383 514 0.000279 0.567 515 0.000113 0.120 516 0.000254 0.209 517 0.000259 0.252 518 0.000164 0.224 519 0.000157 0.116 520 0.000128 0.095 521 0.000133 0.174 522 0.000142 0.110 523 0.000158 0.260 524 - 0.135 525 0.000142 0.087 526 0.000144 0.289 527 0.000804 2.190 528 0.000162 0.140 529 0.005565 2.840 530 0.001200 0.530 531 0.000141 0.138

Example number Mcl-1 HTRF IC ₅₀ (μM) OPM-2 10% FBS IC ₅₀ IP (μM) 100001 0.000055 0.124 100002 0.000071 0.041 100003 0.00042 0.238 100004 0.000072 0.120 100005 0.000091 0.062 100006 0.000081 0.131 100007 0.000367 0.142 100008 0.000170 0.541 100009 0.000128 0.216 100010 0.000077 0.142 100011 0.000153 0.134 100012 0.000275 1.131 100013 0.000199 0.068 100014 0.000228 0.330 100015 0.001040 1.003 100016 0.000182 0.132 100017 0.000039 0.040 100018 0.000061 0.049 100019 0.000182 0.058 100020 0.000032 0.085 100021 0.001053 - 100022 0.000861 - 100023 0.003940 - 100024 0.006155 - 100025 0.002348 - 100026 0.002145 - 100027 0.007340 - 100028 0.001257 - 100029 0.008733 - 100030 0.010355 - 100031 0.007450 - 100032 0.000442 - 100033 0.002815 - 100034 0.000877 - 100035 0.000601 1.470 100036 0.000889 1.980 100037 0.001805 1.920 100038 0.001655 2.560 100039 0.000563 0.744 100040 0.002745 4.950 100041 0.003365 4.990 100042 0.004860 2.220 100043 0.001670 7.280 100044 0.031100 7.290 100045 0.000308 0.342 100046 0.003760 0.976 100047 0.005150 2.540 100048 0.000187 0.551 100049 0.001261 2.150 100050 0.001282 3.824 100051 0.000217 0.502 100052 0.000191 0.424 100053 0.000294 0.609 100054 0.004110 9.060 100055 0.001270 4.630 100056 0.000424 1.680 100057 0.000568 2.600 100058 0.001760 3.360 100059 0.011900 3.450 100060 0.004010 5.980 100061 0.000780 0.529 100062 0.004250 9.940 100063 0.002320 2.260 100064 0.002540 3.730 100065 0.004855 7.390 100066 0.001430 3.820 100067 0.001009 0.271 100068 0.004410 0.765 100069 0.000457 0.250 100070 0.004855 1.070 100071 0.001540 0.588 100072 0.000451 1.720 100073 0.000346 1.197 100074 0.000731 3.020 100075 0.000671 1.817 100076 0.009655 2.670 100077 0.000190 0.052 100078 0.000409 2.720 100079 0.000343 0.713 100080 0.000610 0.818 100081 0.007330 5.930 100082 0.000539 0.727 100083 0.000179 0.123 100084 0.000745 1.488 100085 0.000245 0.288 100086 0.000537 0.390 100087 0.000864 0.187 100088 0.002125 1.340 100089 0.000348 0.325 100090 0.000795 0.798 100091 0.001195 1.350 100092 0.004015 2.210 100093 0.000291 0.554 100094 0.003835 4.380 100095 0.000148 0.113 100096 0.000624 0.517 100097 0.000081 5.230 100098 0.000231 0.748 100099 0.000659 0.349 100100 0.002100 1.325 100101 0.000062 2.595 100102 0.000990 1.430 100103 0.000325 0.778 100104 0.000599 0.250 100105 0.005930 3.660 100106 0.000143 0.121 100107 0.000296 0.181 100108 0.000436 0.358 100109 0.000486 2.140 100110 0.001480 0.686 100111 0.000352 0.687 100112 0.001295 1.800 100113 0.000182 0.070 100114 0.001052 0.491 100115 0.004485 2.840 100116 0.003775 5.940 100117 0.002405 3.170 100118 0.004440 3.950 100119 0.001720 1.570 100120 0.000067 0.635 100121 0.000056 2.530 100122 0.000098 1.190 100123 0.000092 2.660 100124 0.000323 0.270 100125 0.000430 0.555 100126 0.000183 0.041 100127 0.000175 0.108 100128 0.000089 0.217 100129 0.002400 4.870 100130 0.002690 2.170 100131 0.000163 0.144 100132 0.000543 0.675 100133 0.000885 0.984 100134 0.000845 3.510 100135 0.000173 0.161 100136 0.000368 0.556 100137 0.000365 2.820 100138 0.000549 0.342 100139 0.002585 0.974 100140 0.000486 0.299 100141 0.001058 1.370 100142 0.000717 0.663 100143 0.001870 3.270 100144 - 0.208 100145 0.000357 0.945 100146 0.000515 0.347 100147 0.000305 0.666 100148 0.000113 0.239 100149 0.000214 0.186 100150 0.001685 1.430 100151 0.000120 0.071 100152 0.000449 0.377 100153 0.000738 4.660 100154 0.001720 1.070 100155 0.000225 0.332 100156 0.000410 0.568 100157 0.004810 3.210 100158 0.000298 0.260 100159 0.000559 0.591 100160 0.000169 0.078 100161 0.000355 0.757 100162 0.003470 2.870 100163 0.002790 1.000 100164 0.000917 0.967 100165 0.000455 0.579 100166 0.001765 0.945 100167 0.000377 0.339 100168 0.000249 0.196 100169 0.004825 2.270 100170 0.012100 7.820 100171 0.000578 0.868 100172 0.001295 1.570 100173 0.000539 0.379 100174 0.002025 1.910 100175 0.000149 0.452 100176 0.000480 0.603 100177 0.000258 0.259 100178 0.000432 0.237 100179 0.005810 0.840 100180 0.004917 4.425 100181 0.000537 0.226 100182 0.000863 0.827 100183 0.001340 2.245 100184 0.000717 0.179 100185 0.008883 5.130 100186 0.000377 0.312 100187 0.002760 3.110 100188 0.000877 0.735 100189 0.000820 0.701 100190 0.004790 2.480 100191 0.001600 0.557 100192 0.000192 0.149 100193 0.000856 1.300 100194 0.000613 0.619 100195 0.001075 0.625 100196 0.000461 0.358 100197 0.000774 2.460 100198 0.000307 0.399 100199 0.000166 0.148 100200 0.000213 1.070 100201 0.000086 0.307 100202 0.000352 0.928 100203 0.000285 0.491 100204 0.001655 5.270 100205 0.000206 0.068 100206 0.001260 1.750 100207 0.000141 0.215 100208 0.000431 0.318 100209 0.002675 3.380 100210 0.003475 3.360 100211 0.001435 4.780 100212 0.000901 1.620 100213 0.002845 2.020 100214 0.000143 0.095 100215 0.000595 1.250 100216 0.000311 0.374 100217 0.000183 0.130 100218 0.000621 0.675 100219 0.000401 0.974 100220 0.007415 6.840 100221 0.000525 0.776 100222 0.000182 0.222 100223 0.001410 2.150 100224 0.000345 0.385 100225 0.000639 0.882 100226 0.001395 0.849 100227 0.000423 0.191 100228 0.000558 3.300 100229 0.000356 1.490 100230 0.000473 0.544 100231 0.000312 0.350 100232 0.000152 0.389 100233 0.001040 0.257 100234 0.000237 0.449 100235 0.001345 0.644 100236 0.001096 0.933 100237 0.001740 0.996 100238 0.000474 0.747 100239 0.000333 3.740 100240 0.000385 0.266 100241 0.000365 0.401 100242 0.002145 1.450 100243 0.011500 8.670 100244 0.000182 0.049 100245 0.001715 1.980 100246 0.000326 0.114 100247 0.000542 0.624 100248 0.011050 6.680 100249 0.002995 2.270 100250 0.000136 0.082 100251 0.003290 3.730 100252 0.000112 0.077 100253 0.000149 0.544 100254 0.004070 2.150 100255 0.014450 5.020 100256 0.005040 1.200 100257 0.000180 0.080 100258 0.000553 0.519 100259 0.006180 1.250 100260 0.000408 0.094 100261 0.001220 0.533 100262 0.000134 0.433 100263 0.001830 3.390 100264 0.000384 0.600 100265 0.000439 0.441 100266 0.000292 0.571 100267 0.000166 0.274 100268 0.003440 3.810 100269 0.000908 1.230 100270 0.000776 3.72 100271 0.002480 6.120 100272 0.000401 0.349 100273 0.005655 8.660 100274 0.000377 0.543 100275 0.000113 0.309 100276 0.000326 1.528 100277 0.000266 0.448 100278 0.000458 0.333 100279 0.000777 3.25 100280 0.000368 0.305 100281 0.000117 0.352 100282 0.000268 1.280 100283 0.000143 0.806 100284 0.000285 0.396 100285 0.000241 0.642 100286 0.000471 1.580 100287 0.000494 1.870 100288 0.000103 0.089 100289 0.000878 3.960 100290 0.000116 0.259 100291 0.000137 0.281 100292 0.000115 0.672 100293 0.000522 0.726 100294 0.000118 0.116 100295 0.000279 0.302 100297 0.000115 0.168 100298 0.000140 0.199 100299 0.000350 0.623 100300 0.000109 0.235 100301 0.001315 1.930 100302 0.003805 4.880 100303 0.003640 7.330 100304 0.000311 0.464 100305 0.000473 1.140 100306 0.000124 0.278 100307 0.000049 1.030 100308 0.000033 1.170 100309 0.000244 0.385 100310 0.000152 0.120 100311 0.001030 1.190 100312 0.000088 0.234 100313 0.000129 0.143 100314 0.002925 2.290 100315 0.000200 0.153 100316 0.000276 0.375 100317 0.000188 0.157 100318 0.000095 0.114 100319 0.000126 0.506 100320 0.001200 2.140 100321 0.000209 0.285 100322 0.00223 1.54 100323 0.000477 1.250 100324 0.000244 1.170 100325 0.000182 0.482 100326 0.000615 0.334 100327 0.000295 0.550 100328 0.000261 0.180 100329 0.005023 1.560 100330 0.000083 8.260 100331 0.000192 8.260 100332 0.006465 4.31 100333 0.002100 2.170 100334 0.003273 1.470 100335 0.000319 0.165 100336 0.001123 1.810 100337 0.001608 2.410 100338 0.000502 1.920 100339 0.000186 1.380 100340 0.000779 0.308 100341 0.0041 1.94 100342 0.001685 0.782 100343 0.002510 0.617 100344 0.000309 0.290 100345 0.002420 0.218 100346 0.000735 0.248 100347 0.000689 1.080 100348 0.000135 0.125 100349 0.00115 0.058 100350 0.000489 0.554 100351 0.000115 2.02 100352 0.002750 0.246 100353 0.000348 0.151 100354 0.000109 0.147 100355 0.000535 0.776 100356 0.000084 0.071 100357 0.000224 0.399 100358 0.000118 0.081 100359 0.001200 1.540 100360 0.000848 1.230 100361 0.000208 0.155 100362 0.000888 2.1 100363 0.001383 3.810 100364 0.001160 1.680 100365 0.000257 0.245 100366 0.000198 0.168 100367 0.000371 0.604 100368 0.000377 0.611 100369 0.00283 9.92 100370 0.000153 0.258 100371 0.00039 0.307 100372 0.000165 0.833 100373 0.000318 0.736 100374 0.000289 0.433 100375 0.000070 0.176 100376 0.000150 0.362 100377 0.000107 0.182 100378 0.000037 0.111 100379 0.000060 0.071 100380 0.000208 0.137 100381 0.000328 2.910 100382 0.000471 0.312 100383 0.000264 3.430 100384 0.000821 0.729 100385 0.000144 0.144 100386 0.004017 7.27 100387 0.000175 3.760 100388 0.001167 2.160 100389 0.000101 0.114 100390 0.000186 0.649 100391 0.000441 0.282 100392 0.000112 0.129 100393 0.000164 0.211 100394 0.000242 0.622 100395 0.000056 0.040 100396 0.000272 1.470 100397 0.000198 0.404 100398 0.000618 0.457 100399 0.000280 2.810 100400 0.000838 1.320 100401 0.001797 8.390 100402 0.000098 0.133 100403 0.000226 0.39 100404 0.002553 8.15 100405 0.000545 1.120 100406 0.000360 0.747 100407 0.000278 0.516 100408 0.001353 5.62 100409 0.000124 0.206 100410 0.000127 0.297 100411 0.000584 2.1 100412 0.000097 0.249 100413 0.000228 0.556 100414 0.000626 1.270 100415 0.001950 2.285 100416 0.000092 0.086 100417 0.000345 0.379 100418 0.000098 0.141 100419 0.000277 0.416 100420 0.000112 0.161 100421 0.003926 4.93 100422 0.000174 0.182 100423 0.000056 0.099 100424 0.000249 0.469 100425 0.000165 0.717 100426 0.000197 0.110 100427 0.000209 0.342 100428 0.000210 0.218 100429 0.000176 1.420 100430 0.000057 0.358 100431 0.000043 0.290 100432 0.000228 0.711 100433 0.000026 0.296 100434 0.000162 0.482 100435 0.000055 0.305 100436 0.000076 0.335 100437 0.000073 0.531 100438 0.000169 0.547 100439 0.000619 2.640 100440 0.000398 0.354 100441 0.000133 0.154 100442 0.000921 3.870 100443 0.000070 0.156 100444 0.000098 0.646 100445 0.000040 0.098 100446 0.000126 0.345 100447 0.000050 0.184 100448 0.000373 1.920 100449 0.000071 0.171 100450 0.000336 1.910 100451 0.000111 0.412 100452 0.000077 0.157 100453 0.000927 2.930 100454 0.000652 0.802 100455 0.000087 0.140 100456 0.000565 1.230 100457 0.000331 0.967 100458 0.000210 0.418 100459 0.000685 0.732 100460 0.000095 0.433 100461 0.000042 0.382 100462 0.000304 0.652 100463 0.000383 1.130 100464 - 1.530 100465 0.000121 0.729 100466 0.000043 1.440 100467 0.000303 0.516 100468 0.000393 0.943 100469 0.000085 0.325 100470 0.000576 9.65 100471 0.000281 0.299 100472 0.000651 0.357 100473 0.000974 0.178 100474 0.000405 0.387 100475 0.001365 2.710 100476 - 1.340 100477 0.000313 0.159 100478 0.003470 4.090 100479 0.000758 0.332 100480 0.000176 0.221 100481 0.000094 0.152 100482 0.000183 0.105 100483 0.001664 1.690 100484 0.003850 3.370 100485 0.000192 0.272 100486 0.000381 0.102 100487 0.000436 0.340 100488 0.000389 0.346 100489 0.000880 0.182 100490 0.000292 0.511 100491 0.000208 0.308 100492 0.000749 0.436 100493 0.000322 0.512 100494 0.000078 0.089 100495 0.000462 0.539 100496 0.002665 5.060 100497 0.000064 0.106 100498 0.000885 1.660 100499 0.000509 1.120 100500 0.000049 0.071 100501 0.000090 0.518 100502 0.000290 0.393 100503 0.000493 0.706 100504 0.000803 1.890 100505 0.000165 0.137 100506 0.000497 1.270 100507 0.000430 0.490 100508 0.002734 2.500 100509 0.000057 0.361 100510 0.000070 0.379 100511 0.000070 0.430 100512 0.000415 1.490 100513 0.000071 0.288 100514 0.000088 0.231 100515 0.000132 0.585 100516 0.003360 1.900 100517 0.001059 3.460 100518 0.000427 0.668 100519 0.000175 0.138 100520 0.000549 1.690 100521 0.000197 0.296 100522 0.000144 0.538 100523 0.000812 0.622 100524 0.000990 0.842 100525 0.003305 1.430 100526 0.000387 0.826 100527 0.003595 3.570 100528 0.000138 0.257 100529 0.000287 0.245 100530 0.000171 0.448 100531 0.000083 0.172 100532 0.000053 8.637 100533 0.008565 3.990 100534 0.000799 0.542 100535 0.000570 0.964 100536 0.000204 0.826 100537 0.000115 0.256 100538 0.001470 2.400 100539 0.000144 0.727 100540 0.000275 0.320 100541 0.000760 0.826 100542 0.000229 0.902 100543 0.000451 0.821 100544 0.000171 0.306 100545 0.000153 0.231 100546 0.000084 0.440 100547 0.000031 1.860 100548 0.000064 8.410 100549 0.002570 0.545 100550 0.000059 6.859 100551 0.000174 0.142 100552 0.000065 0.957 100553 0.001040 2.790 100554 0.000231 0.519 100555 0.000101 0.113 100556 0.000113 0.734 100557 0.000093 0.299 100558 0.000086 0.274 100559 0.000113 1.030 100560 0.000041 2.020 100561 0.000275 0.673 100562 0.000057 0.532 100563 0.000065 0.510 100564 0.000333 1.430 100565 0.001540 2.060 100566 0.000142 0.590 100567 0.000125 0.249 100568 0.000431 1.540 100569 0.002479 2.000 100570 0.003380 5.050 100571 0.000076 0.922 100572 0.000174 1.160 100573 0.002070 7.390 100574 0.001420 4.320 100575 0.001300 2.500 100576 0.001150 4.090 100577 0.000045 2.020 100578 0.000089 0.595 100579 0.000214 0.757 100580 0.000877 6.580 100581 0.000363 1.540 100582 0.000197 1.120 100583 0.000124 0.411 100584 0.000139 0.349 100585 0.000057 0.696 100586 0.000074 0.453 100587 0.000136 0.177 100588 0.000075 0.117 100589 0.001835 3.330 100590 0.000086 0.501 100591 0.000075 0.060 100592 0.000275 0.139 100593 0.000464 0.215 100594 0.000143 0.241 100595 0.000157 0.133 100596 0.000229 0.186 100597 0.000263 0.577 100598 0.000077 0.188 100599 0.001150 1.140 100600 0.000445 0.528 100601 0.000114 0.239 100602 0.000800 2.330 100603 0.000651 1.570 100604 0.000723 4.110 100605 0.003245 7.950 100606 0.000209 0.428

In vivo data

Tumor Pharmacodynamics (PD)

1-7 show the PD results of the cited examples. Reference compound 1, which is Amgen's MCl-1 inhibitor inhibitor compound made by one of the general schemes outlined in US Pat. No. 9,562,061 (incorporated herein by reference), is (1S, 3'R, 6'R, 7'S, 8 ' E, 12'R) -6-Chloro-12'-ethyl-7'-methoxy-3,4-dihydro-2H, 15'H-spiro [naphthalene-1,22 '-[20] oxa [13 ] Thia [1,14] diaza tetracyclo [14.7.2.0-3,6-0.0-19,24-] pentacosa [8,16,18,24] tetraen] -15'-one 13 ', 13'-dioxide.

Female athymic nude mice (Charles River Laboratories, Inc., Indianapolis, Indiana) were subcutaneously inoculated with 5 × 10 ⁶ OPM-2 Luc cells. When the tumor size reached 300-500 mm ³ , mice were randomly assigned to treatment groups and tumors were harvested 6 hours after one dose of various concentrations of compound. Tumor lysates were analyzed for active Bak using a sandwich ELISA format (active Bak MSD plate, catalog number N45ZA-1; Bak detection antibody Abcam, catalog number Ab53153; and sulfur-tag by MSD) and on an MSD reader (S16000). Read. The vertical term represents the luminescence level (cps) (n = 3 per group). Statistical significance was determined in comparison to vehicle control by Oneway ANOVA followed by Dunnett's post hoc. Black rhombus represents drug plasma concentration and circles represent drug concentration in tumor.

OPM-2 Xenograft

Examples 8-13 show xenograft data of various compounds of the invention. Female athymic nude mice (Charles River Laboratories, Inc., Indianapolis, Indiana) were subcutaneously inoculated with 5 × 10 ⁶ OPM-2 Luc cells. When the average volume of tumors reached approximately 155-183 mm ³ , animals were randomized (n = 10 per group) and various concentrations of test compounds (unless otherwise indicated) were obtained by oral gavage. Once daily (10-12 days). Tumor volume and body weight were recorded twice a week using electronic calipers and analytical balances. Statistical analysis was performed using Repeated Measures ANOVA (RMANOVA) followed by Dunnett's post test.

The foregoing descriptions are merely illustrative of the invention and are not intended to be limiting to the compounds, compositions and methods disclosed herein. Changes and modifications apparent to those skilled in the art are intended to be included within the scope and nature of the invention as defined in the appended claims. From the foregoing description, those skilled in the art can readily identify essential features of the present invention, and various changes and modifications of the present invention can be made to suit various applications and conditions without departing from its spirit and scope. All patents and other publications cited herein are incorporated by reference in their entirety.

Claims (61)

Compound of formula (I)
Formula I;

As stereoisomers thereof, pharmaceutically acceptable salts thereof, or pharmaceutically acceptable salts of stereoisomers thereof,
In the formula,
Z is C or N;
Q is O, S, CR ^WA R ^WB , or NR ^a R ^b ;
W is CR ^WA R ^WB , —C═O or absent;
R ^WA and R ^WB are independently selected from H, -C _1-3 alkyl, -C _1-3 alkenyl, -C _1-3 alkynyl, halo, -OH, or -OC _1-3 alkyl;
symbol

B is a single or double chemical bond which may be cis or trans;
R ¹ is H, halo, C _1-6 alkylhalo, C _1-6 alkyl, C _2-6 alkenyl,-(CH ₂ CH ₂ O) _n R ^a , -SO ₂ R ^a , -C (= O) R ^a , -C (= 0) OR ^a , or -C (= 0) NR ^a R ^b ;
R ² is H, halo, C _1-6 haloalkyl, C _1-6 alkyl, OC _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, -C _1-6 alkyl-OC _{1- 6} alkyl,-(CH ₂ CH ₂ O) _n R _a , -SO ₂ R _a , -C (= 0) R ^a , -C (= 0) OR ^a , -OC (= 0) R ^a , -C (═O) NR ^a R ^b , 6- to 12-membered aryl or heteroaryl, 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, or 3- to 12-membered cycloalkenyl, 3 -Membered to 12-membered monocyclic or bicyclic cycloalkyl, or 3-membered to 12-membered monocyclic or bicyclic heterocycloalkyl group, wherein the heteroaryl, spiroheterocycloalkyl or heterocycloalkyl group is independently from O, N or S With 1, 2, 3 or 4 heteroatoms selected, the cycloalkyl, spirocycloalkyl, spirocyclocycloalkyl, and heterocycloalkyl groups may comprise C═O groups, further spiroheterocycloalkyl and heterocycloalkyl groups Is S = O or SO ₂ May comprise;
R ³ is H, —C _1-6 alkylhalo, —C _1-6 alkyl, —C _2-6 alkenyl, — (CH ₂ CH ₂ O) _n R ^a , —C (═O) R ^a , -C (= 0) OR ^a , or -C (= 0) NR ^a R ^b ;
R ^2B , R ^2C , R ⁴ , R ⁵ , R ⁶ , R ⁷ , and R ⁸ are each H, halo, —C _1-6 haloalkyl, —C _1-6 alkyl, —OC _1-6 alkyl, — C _2-6 alkenyl, -C _1-6 alkyl, -OC _{1-6 alkyl, - (CH 2 CH 2 O} ) n R a, -SO 2 R a, -C (= O) R a, - C ( = O) OR ^a , -OC (= O) R ^a , -C (= O) NR ^a R ^b , 6- to 12-membered aryl or heteroaryl, 5- to 12-membered spirocycloalkyl or spiro Heteroaryl, independently selected from heterocycloalkyl, 3- to 12-membered cycloalkenyl, 3- to 12-membered monocyclic or bicyclic cycloalkyl, or 3- to 12-membered monocyclic or bicyclic heterocycloalkyl group, heteroaryl , The spiroheterocycloalkyl and heterocycloalkyl groups have 1, 2, 3 or 4 heteroatoms independently selected from O, N or S, and the cycloalkyl, spirocycloalkyl, spirocyclocycloalkyl, and heterocycloalkyl groups are C May comprise a ═O group, and further comprises spiroheterocycloalkyl and hetero Claw alkyl group may include a S = O or SO _2, and;
Alternatively, R ³ and R ⁴ together with the atoms to which they are attached form a 5-membered to 12-membered ring, wherein in addition to the S and N atoms present in the ring, a heteroatom selected from N, O or S atoms is optionally To form a containing ring, the ring may optionally contain at least one double bond, and the ring may be substituted with 0, 1, 2, or 3 R ^3A substituents;
R ^3A is H, halo, -OH, C _1-6 haloalkyl, C _1-6 alkyl, OC _1-6 alkyl, C _2-6 alkenyl, -C _1-6 alkyl -OC _1-6 alkyl,- (CH ₂ CH ₂ O) _n R ^a , -SO ₂ R ^a , -C (= 0) R ^a, -C (= 0) OR ^a , -OC (= 0) R ^a , or -C (= 0) ) NR ^a R ^b ;
Each of R ^4A , R ^5A , R ^6A , R ^7A , and R ^8A is independently selected from H, OH, halo, or —C _1-6 alkyl;
R ^7A and R ^8A are absent when b is a double chemical bond;
Alternatively, R ⁷ and R ⁸ may form a 3- to 12-membered ring together with the atoms to which they are attached, and the ring may optionally contain at least one double bond;
R ⁹ is H, OH,-(= O), -C _1-6 haloalkyl, -C _1-6 alkyl, -C _1-6 alkenylene,-(CH ₂ CH ₂ O) _n R ^a , -C ^{(= O) R a, -} C (= O) OR a, -C (= O) NR a R b, -C 1-6 alkyl, -OC _1-6 alkyl, cyano, 6-membered to 12-membered Aryl or heteroaryl, 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, 3- to 12-membered cycloalkenyl, 3- to 12-membered monocyclic or bicyclic cycloalkyl, or 3-membered to Independently selected from a 12-membered monocyclic or bicyclic heterocycloalkyl group, a heteroaryl, spiroheterocycloalkyl or heterocycloalkyl group has 1, 2, 3 or 4 heteroatoms independently selected from O, N or S, and cyclo Alkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkyl groups may comprise C═O groups, and further spiroheterocycloalkyl and heterocycloalkyl groups may comprise S═O or SO ₂ ;
R ^9A is H, -OH, halo, cyano, -C _1-6 haloalkyl, -C _1-6 alkyl, -C ₂ -C ₆ alkenyl, -C ₂ -C ₆ alkynyl,-(CH ₂ CH ₂ O) _n R ^a , -P (= O) OR ^a OR ^b , -CSR ^a , -CS (= O) R ^a , -SR ^a , -SOR ^a , -OSO ₂ R ^a , -SO ₂ R ^a ,-(CH ₂ CH ₂ O) _n CH ₃ ,-(= O), -C (= O), -C (= O) R ^a , -C (= O) OR ^a , -C (= O ) NR ^a R ^b , -CH ₂ -NR ^a R ^b , -NR ^a R ^b , -C _1-6 alkyl-OC _1-6 alkyl, -OC _1-6 alkyl, -OC _1-6 alkyl-OC _{1 -6} alkyl, phenyl, 6- to 12-membered aryl, 6- to 12-membered heteroaryl, 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, 3- to 12-membered cycloal Independently selected from kenyl, 3-membered to 12-membered monocyclic or bicyclic cycloalkyl, or 3-membered to 12-membered monocyclic or bicyclic heterocycloalkyl group, heteroaryl, spiroheterocycloalkyl and heterocycloalkyl group being O, N Or having 1, 2, 3 or 4 heteroatoms independently selected from S, cycloalkyl, spirocycle Alkyl, spiro-heterocycloalkyl, and heterocycloalkyl group is further number, and comprise a group may contain a double bond and the C = O spiro heterocycloalkyl and heterocycloalkyl group may comprise a S = O or SO _2, and ;
R ^9A is not H when W is absent;
The aryl, heteroaryl, cycloalkyl, heterocycloalkyl, spirocycloalkyl and ^{spirterocycloalkyl} groups of the R ^9A substituent are unsubstituted or substituted with OH, halo, -NR ^c R ^d , -C _1-6 alkyl, -C ₂ -C ₆ alkenyl, -C ₂ -C ₆ alkynyl, -OC _1-6 alkyl, -C _1-6 alkyl-OH, -C _1-6 alkyl-OC _1-6 alkyl, C _1-6 haloalkyl,- O-haloC _1-6 alkyl, -SO ₂ R ^c , -CN, -C (= 0) NR ^c R ^d , -C (= 0) R ^c , -OC (= 0) R ^a , -C ( = O) OR ^c , 6- to 12-membered aryl, 6- to 12-membered heteroaryl, 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, 3- to 12-membered cycloal May be substituted with 1, 2, 3 or 4 R ¹⁰ substituents independently selected from kenyl, 3- to 12-membered monocyclic or bicyclic cycloalkyl, or 3- to 12-membered monocyclic or bicyclic heterocycloalkyl groups, Heteroaryl, spiroheterocycloalkyl, and heterocycloalkyl groups are 0, independently selected from O, N or S, Having 1, 2, 3 or 4 heteroatoms, the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkyl groups can comprise C═O groups, and further the spiroheterocycloalkyl and heterocycloalkyl groups May comprise S═O or SO ₂ ;
Alternatively, R ⁷ and R ^9A together with the atoms to which they are attached may form a 3-membered to 12-membered ring, and the ring may optionally contain at least one double bond;
Alternatively, R ⁹ and R ^9A form a 3- to 12-membered monocyclic or bicyclic ring together with Q, W and C to which W and Q bond, with hetero in addition to Q selected from N, O or S May form a ring optionally containing an atom, the ring may contain a double bond, the ring may optionally include a C═O group, and further the ring may be substituted by 1, 2, or 3 R ¹¹ substituents May be optionally substituted;
R ¹¹ is H, -OH, halo, -C _1-6 alkyl, -OC _1-6 alkyl, -C _1-6 alkyl-OH, -C _1-6 alkyl-OC _1-6 alkyl, -C _{1- 6} haloalkyl, -O-haloC _1-6 alkyl, -SO ₂ R ^c , -CN, -NR ^c R ^d , -C (= 0) NR ^c R ^d , -C (= 0) R ^c ,- OC (= 0) R ^c , -C (= 0) OR ^c , 6- to 12-membered aryl or heteroaryl, 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, 3- to 12 Independently selected from -membered cycloalkenyl, 3-membered to 12-membered monocyclic or bicyclic cycloalkyl, or 3-membered to 12-membered monocyclic or bicyclic heterocycloalkyl group, heteroaryl, spiroheterocycloalkyl, and heterocyclo The alkyl group has 1, 2, 3 or 4 heteroatoms independently selected from O, N or S, and the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkyl groups can comprise double bonds and cyclo Alkyl, spirocycloalkyl, spiroheterocycloalkyl, And the heterocycloalkyl group may comprise a C═O group, and further the spiroheterocycloalkyl and heterocycloalkyl group may comprise S═O or SO ₂ ;
R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ^4A , R ^5A , R ^6A , R ^7A , R ^8A , R ^9A C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl and —OC _1-6 alkyl of any one of the R ^WA and R ^WB substituents may be unsubstituted or substituted with OH, —OC _1-6 alkyl, -C _1-6 alkyl-OC _1-6 alkyl, halo, -O-haloC _1-6 alkyl, -CN, -NR ^a R ^b ,-(NR ^a R ^b R ^c ) _n , -OSO ₂ R ^a , -SO ₂ R ^a ,-(CH ₂ CH ₂ O) _n CH ₃ ,-(= O), -C (= O), -C (= O) R ^a , -OC (= O) R ^a , -C (= 0) OR ^a , -C (= 0) NR ^a R ^b , -O-SiR ^a R ^b R ^c , -SiR ^a R ^b R ^c , -O- (3- to 10-membered hetero Cycloalkyl), 6-membered to 12-membered aryl or heteroaryl, 5-membered to 12-membered spirocycloalkyl or spiroheterocycloalkyl, 3-membered to 12-membered cycloalkenyl, 3-membered to 12-membered Monocyclic or bicyclic cycloalkyl, or substituted by 1, 2 or 3 R ¹² substituents independently selected from 3- to 12-membered monocyclic or bicyclic heterocycloalkyl groups, heteroaryl, spi The loheterocycloalkyl and heterocycloalkyl groups have 1, 2, 3 or 4 heteroatoms independently selected from O, N or S, and the cycloalkyl, spirocycloalkyl, spirocyclocycloalkyl, and heterocycloalkyl groups are C = May comprise an O group, and further the spiroheterocycloalkyl and heterocycloalkyl groups may comprise S═O or SO ₂ ;
R ² , R ⁴ , R ⁵ , Aryl, heteroaryl, cycloalkyl, heterocycloalkyl, spirocycloalkyl and any one of R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ^9A , R ¹⁰ , R ¹¹ , R ¹² , R ^WA and R ^WB substituents and Spiroheterocycloalkyl groups are unsubstituted or substituted with OH, halo, -NR ^c R ^d , -C _1-6 alkyl, -OC _1-6 alkyl, -C _1-6 alkyl-OH, -C _1-6 alkyl-OC _{1 -6} alkyl, C _1-6 haloalkyl, -O-haloC _1-6 alkyl, -SO ₂ R ^c , -CN, -C (= 0) NR ^c R ^d , -C (= 0) R ^c , -OC (= 0) R ^a , -C (= 0) OR ^c , 6- to 12-membered aryl or heteroaryl, 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, 3-membered to With 1, 2, 3 or 4 R ¹³ substituents independently selected from 12-membered cycloalkenyl, 3- to 12-membered monocyclic or bicyclic cycloalkyl, or 3-membered to 12-membered monocyclic or bicyclic heterocycloalkyl group may be substituted, a heteroaryl group, spiro-heterocycloalkyl, heteroaryl, and cycloalkyl group of R ¹³ is O, N or S robu Independently has a selected one, two, three or four heteroatoms, heterocycloalkyl group of R ¹³ cycloalkyl, spiro cycloalkyl, and spiro heterocycloalkyl group or R ¹³ is additionally can comprise a C = O, Spiroheterocycloalkyl and heterocycloalkyl groups may comprise S═O or SO ₂ ;
Each of R ^a , R ^b , R ^c , and R ^d is independently hydrogen, OH, —C _1-6 alkyl, —C _2-6 alkenyl, —C _2-6 alkynyl, —C _1-6 alkyl -NR ¹⁴ R ¹⁴ , -NR ¹⁴ R ¹⁴ , -SO ₂ R ¹⁴ ,-(CH ₂ CH ₂ O) _n CH ₃ ,-(= O), -C (= O) R ¹⁴ , -OC (= O ) R ¹⁴ , -C (= 0) OR ¹⁴ , -C (= 0) NR ¹⁴ R ¹⁴ , -C _1-6 haloalkyl, -O-haloC _1-6 alkyl, -C _1-6 alkyl-OC _1-6 alkyl, benzyl, phenyl, -C _1-6 alkyl C (= 0) OH, -C _1-6 alkyl-C (= 0) -OC _1-6 alkyl, -C _1-6 alkyl-cycloalkyl , -C _1-6 alkyl-heterocycloalkyl, -C _1-6 alkyl-6- to 12-membered aryl, -C _1-6 alkyl-6- to 12-membered heteroaryl, 6- to 12 -Membered aryl or heteroaryl, 5-membered to 12-membered spirocycloalkyl or spiroheterocycloalkyl, or 3-membered to 12-membered cycloalkenyl, 3-membered to 12-membered monocyclic or bicyclic cycloalkyl, or 3 A -membered to 12-membered monocyclic or bicyclic heterocycloalkyl group, and heteroaryl, spirohterocycloalkyl, heterocycloalkyl group or -C _1-6 alkyl The heterocycloalkyl group has 1, 2, 3 or 4 heteroatoms independently selected from O, N or S; The cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, heterocycloalkyl group of R ^a , R ^b , R ^c , and R ^d , or the heterocycloalkyl group of -C _1-6 alkyl-heterocycloalkyl group, may comprise a double bond. May comprise a C═O group, and the spiroheterocycloalkyl or heterocycloalkyl may comprise S═O or SO ₂ ;
Of R ^a, R ^b, R ^c, and R ^d of the alkyl, aryl, heteroaryl, spiro cycloalkyl, spiro-heterocycloalkyl, cycloalkyl, or heterocycloalkyl group, and R ^a, R ^b, R ^c, and R ^d The heterocycloalkyl group of a -C _1-6 alkyl-heterocycloalkyl group may be unsubstituted or substituted with 1, 2, 3, or 4 R ¹⁴ substituents, each R ¹⁴ being H, -OH, -N = N = N, halo, -C _1-6 alkyl, -C _1-6 haloalkyl, -OC _1-6 alkyl, -C _1-6 alkyl-OC _1-6 alkyl, -C _1-6 haloalkyl, -O -HaloC _1-6 alkyl, phenyl, tolyl, -C (= 0) C _1-6 alkyl, -C (= 0) OC _1-6 alkyl, N (CH ₃ ) ₂ or -SO ₂ -N (CH ₃ ) independently selected from ₂ ;
n is independently at each occurrence an integer of 1, 2, 3 or 4, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of its stereoisomer. The compound of claim 1, wherein the compound is of formula II
Formula II;

A compound having, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof. The compound of claim 1 or 2, wherein the compound is of formula IIa
Formula IIa;

A compound having, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof. The compound of claim 1 wherein the compound is

or

A compound having a structure selected from or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof. Compound of formula (I ')
Formula I ';

Or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof,
In the formula,
Z is C or N;
Q is O or S;
W is CR ^WA R ^WB or ^C═O ;
R ^WA and R ^WB are independently selected from H, C _1-3 alkyl, halo, -OH, or -OC _1-3 alkyl;
symbol

B is a single or double chemical bond which may be cis or trans;
R ¹ is H, halo, C _1-6 alkylhalo, C _1-6 alkyl,-(CH ₂ CH ₂ O) _n R ^a , -SO ₂ R ^a , -C (= O) R ^a , -C Independently selected from (═O) OR ^a , or —C (═O) NR ^a R ^b ;
R ² is H, halo, -C _1-6 haloalkyl, -C _1-6 alkyl, -OC _1-6 alkyl, -C _2-6 alkenyl, -C _1-6 alkyl-OC _1-6 alkyl, -(CH ₂ CH ₂ O) _n R ^a , -SO ₂ R ^a , -C (= 0) R ^a , -C (= 0) OR ^a , -OC (= 0) R ^a , or -C (= O) NR ^a R ^b ;
R ³ is H, —C _1-6 alkylhalo, —C _1-6 alkyl, —C _2-6 alkenyl, — (CH ₂ CH ₂ O) _n R ^a , —C (═O) R ^a , Independently from -C (= 0) OR ^a , or -C (= 0) NR ^a R ^b ;
R ⁴ , R ⁵ , R ⁶ , R ⁷ , and R ⁸ are each H, halo, -C _1-6 haloalkyl, -C _1-6 alkyl, -OC _1-6 alkyl, -C _2-6 alkenyl , -C _1-6 alkyl-OC _1-6 alkyl,-(CH ₂ CH ₂ O) _n R ^a , -SO ₂ R ^a , -C (= O) R ^a, -C (= O) OR ^a , -OC (= 0) R ^a , -C (= 0) NR ^a R ^b , 6- to 12-membered aryl or heteroaryl, 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, 3- Independently selected from membered to 12-membered cycloalkenyl, 3-membered to 12-membered monocyclic or bicyclic cycloalkyl, or 3-membered to 12-membered monocyclic or bicyclic heterocycloalkyl group, heteroaryl, spiroheterocycloalkyl and Heterocycloalkyl groups have 1, 2, 3 or 4 heteroatoms independently selected from O, N or S, and cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkyl groups can include C═O groups And further spiroheterocycloalkyl and heterocycloalkyl It may comprise a S = O or SO _2, and;
Alternatively, R ³ and R ⁴ together with the atoms to which they are attached form a 5-membered to 12-membered ring, wherein in addition to the S and N atoms present in the ring, a heteroatom selected from N, O or S atoms is optionally To form a containing ring, the ring may optionally contain at least one double bond, and the ring may be substituted with 0, 1, 2, or 3 R ^3A substituents;
R ^3A is H, halo, -OH, C _1-6 haloalkyl, C _1-6 alkyl, OC _1-6 alkyl, C _2-6 alkenyl, -C _1-6 alkyl-OC _1-6 alkyl,- (CH ₂ CH ₂ O) _n R ^a , -SO ₂ R ^a , -C (= O) R ^a , -C (= O) OR ^a , -OC (= O) R ^a , -C (= O) Independently from NR ^a R ^b ;
Each of R ^4A , R ^5A , R ^6A , R ^7A , and R ^8A is independently selected from H, OH, halo, or —C _1-6 alkyl;
R ^7A and R ^8A are absent when b is a double chemical bond;
R ⁹ is H, -C _1-6 haloalkyl, -C _1-6 alkyl, -C _2-6 alkenyl, -C _2-6 alkynyl,-(CH ₂ CH ₂ O) _n R ^a , -C (═O) R ^a , —C (═O) OR ^a , —C (═O) NR ^a R ^b , —C _1-6 alkyl-OC _1-6 alkyl, 6- to 12-membered aryl or hetero Aryl, 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, 3- to 12-membered cycloalkenyl, 3- to 12-membered monocyclic or bicyclic cycloalkyl, or 3- to 12-membered Independently selected from monocyclic or bicyclic heterocycloalkyl groups, heteroaryl, spiroheterocycloalkyl and heterocycloalkyl groups have 1, 2, 3 or 4 heteroatoms independently selected from O, N or S, cycloalkyl, spiro Cycloalkyl, spiroheterocycloalkyl, and heterocycloalkyl groups may comprise C═O groups, and further, spirohterocycloalkyl and heterocycloalkyl groups may comprise S═O or SO ₂ ;
R ^9A is H, C _1-6 haloalkyl, C _1-6 alkyl, -C _2-6 alkenyl, -C _2-6 alkynyl,-(CH ₂ CH ₂ O) _n R ^a , -SO ₂ R ^a , -C (= 0) R ^a , -C (= 0) OR ^a , -C (= 0) NR ^a R ^b , -NR ^a R ^b , -N = N = N, -C _1-6 alkyl -OC _1-6 alkyl, 6- to 12-membered aryl, 6- to 12-membered heteroaryl, 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, 3- to 12-membered cyclo Alkenyl, 3-membered to 12-membered monocyclic or bicyclic cycloalkyl, or 3-membered to 12-membered monocyclic or bicyclic heterocycloalkyl group, and heteroaryl, spirohterocycloalkyl and heterocycloalkyl group are O, Cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkyl groups having 1, 2, 3, or 4 heteroatoms independently selected from N or S, may comprise a C═O group, and further spiro Heterocycloalkyl and heterocycloalkyl groups are S═O or SO May comprise ₂ ;
The aryl, heteroaryl, cycloalkyl, heterocycloalkyl, spirocycloalkyl and ^{spirterocycloalkyl} groups of the R ^9A substituent are unsubstituted or substituted with OH, halo, -NR ^c R ^d , -C _1-6 alkyl, -C ₂ -C ₆ alkenyl, -C ₂ -C ₆ alkynyl, -OC _1-6 alkyl, -C _1-6 alkyl-OH, -C _1-6 alkyl-OC _1-6 alkyl, C _1-6 haloalkyl,- O-haloC _1-6 alkyl, -SO ₂ R ^c , -CN, -C (= 0) NR ^c R ^d , -C (= 0) R ^c , -OC (= 0) R ^a , -C ( = O) OR ^c , 6- to 12-membered aryl, 6- to 12-membered heteroaryl, 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, 3- to 12-membered cycloal May be substituted with 1, 2, 3 or 4 R ¹⁰ substituents independently selected from kenyl, 3- to 12-membered monocyclic or bicyclic cycloalkyl, or 3- to 12-membered monocyclic or bicyclic heterocycloalkyl groups, Heteroaryl, spiroheterocycloalkyl, and heterocycloalkyl groups are 0, independently selected from O, N or S, Having 1, 2, 3 or 4 heteroatoms, the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkyl groups can comprise C═O groups, and further the spiroheterocycloalkyl and heterocycloalkyl groups May comprise S═O or SO ₂ ;
Alternatively, R ⁹ and R ^9A form a 3- to 12-membered monocyclic or bicyclic ring together with Q, W and C to which W and Q bond, with hetero in addition to Q selected from N, O or S May form a ring optionally containing an atom, the ring may contain a double bond, the ring may optionally include a C═O group, and further the ring may be substituted by 1, 2, or 3 R ¹¹ substituents May be optionally substituted;
R ¹¹ is OH, halo, -NR ^c R ^d , -C _1-6 alkyl, -OC _1-6 alkyl, -C _1-6 alkyl-OH, -C _1-6 alkyl-OC _1-6 alkyl, C _1-6 haloalkyl, -O-haloC _1-6 alkyl, -SO ₂ R ^c , -CN, -C (= 0) NR ^c R ^d , -C (= 0) R ^c , -OC (= 0 ) R ^a , -C (═O) OR ^c , 6- to 12-membered aryl or heteroaryl, 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, 3- to 12-membered cycloal Independently selected from kenyl, 3- to 12-membered monocyclic or bicyclic cycloalkyl, or 3- to 12-membered monocyclic or bicyclic heterocycloalkyl groups, heteroaryl, spiroheterocycloalkyl, and heterocycloalkyl groups being O, Cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkyl groups having 1, 2, 3 or 4 heteroatoms independently selected from N or S, may comprise a C═O group, and further spirohetero Cycloalkyl and heterocycloalkyl groups are S = O or May include SO ₂ ;
R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ^4A , R ^5A , R ^6A , R ^7A , R ^8A and R ^9A -C _1-6 alkyl of any of the substituents is unsubstituted or OH, -OC _1-6 alkyl, -C _1-6 alkyl-OC _1-6 alkyl, halo, -O-haloC _1-6 alkyl,- CN, -NR ^a R ^b ,-(NR ^a R ^b R ^c ) _n , -SO ₂ R ^a ,-(CH ₂ CH ₂ O) _n CH ₃ , (= O), -C (= O),- C (= O) R ^a , -OC (= O) R ^a , -C (= O) OR ^a , -C (= O) NR ^a R ^b , -O-SiR ^a R ^b R ^c , -O- (3- to 12-membered heterocycloalkyl), 6- to 12-membered aryl or heteroaryl, 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, 3- to 12-membered cycloal Heteroaryl substituted by 1, 2 or 3 R ¹² substituents independently selected from kenyl, 3- to 12-membered monocyclic or bicyclic cycloalkyl, or 3- to 12-membered monocyclic or bicyclic heterocycloalkyl group Spiroheterocycloalkyl and heterocycloalkyl groups are independent from O, N or S The cycloalkyl, spirocycloalkyl, spirocyclocycloalkyl, and heterocycloalkyl groups having 1, 2, 3 or 4 heteroatoms selected from may further comprise a C═O group, and further spiroheterocycloalkyl and heterocyclo The alkyl group may comprise S═O or SO ₂ ;
R ² , R ⁴ , R ⁵ , The aryl, heteroaryl, cycloalkyl, heterocycloalkyl, spirocycloalkyl and spiroheterocycloalkyl groups of any one of the R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ and R ¹² substituents are unsubstituted or OH , Halo, -C _1-6 alkyl, -OC _1-6 alkyl, -C _1-6 alkyl-OH, -C _1-6 alkyl-OC _1-6 alkyl, C _1-6 haloalkyl, -O-halo C _1-6 alkyl, —SO ₂ R ^c , —NR ^c R ^d , —CN, —C (═O) NR ^c R ^d , —C (═O) R ^c , —OC (═O) R ^a , -C (= 0) OR ^c , -B (OH) ₂ , 6- to 12-membered aryl or heteroaryl, 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, 3- to 12- To be substituted with 1, 2, 3 or 4 R ¹³ substituents independently selected from membered cycloalkenyl, 3-membered to 12-membered monocyclic or bicyclic cycloalkyl, or 3-membered to 12-membered monocyclic or bicyclic heterocycloalkyl group Wherein the heteroaryl, spiroheterocycloalkyl, and heterocycloalkyl groups are independently from O, N, or S With 1, 2, 3 or 4 heteroatoms selected, the cycloalkyl, spirocycloalkyl, spirocyclocycloalkyl, and heterocycloalkyl groups can comprise C═O groups, further spiroheterocycloalkyl and heterocycloalkyl groups May comprise S═O or SO ₂ ;
Each R ^a , R ^b , R ^c , and R ^d is independently H, OH, -C _1-6 alkyl, -C _1-6 alkenyl, -C _2-6 alkynyl, -C _1-6 alkyl -NR ¹⁴ R ¹⁴ , NR ¹⁴ R ¹⁴ , -SO ₂ R ¹⁴ ,-(CH ₂ CH ₂ O) _n CH ₃ , (= O), -C (= O) R ¹⁴ , -OC (= O) R ¹⁴ , -C (= 0) OR ¹⁴ _, -C (= 0) NR ¹⁴ R ¹⁴ , C _1-6 haloalkyl, -O-haloC _1-6 alkyl, -C _1-6 alkyl-OC _1-6 Alkyl, -C _1-6 alkyl-OH, benzyl, phenyl, -C _1-6 alkyl-3-membered to 12-membered heterocycloalkyl, 6-membered to 12-membered aryl or heteroaryl, 5-membered to 12 -Membered spirocycloalkyl or spiroheterocycloalkyl, 3- to 12-membered cycloalkenyl, 3- to 12-membered monocyclic or bicyclic cycloalkyl, or 3- to 12-membered monocyclic or bicyclic heterocycloalkyl group , heteroaryl, spiro-heterocycloalkyl, and heterocycloalkyl group and a -C _1-6 alkyl- is a heterocycloalkyl group of the heterocycloalkyl group is O, N or S 1, 2, 3 or 4 heteroatoms independently selected from And, cycloalkyl, spiro cycloalkyl, spiro-heterocycloalkyl, heterocycloalkyl, and -C _1-6 alkyl-heterocycloalkyl group in heterocycloalkyl group may include a group C = O, spiro-heterocycloalkyl, and additionally Heterocycloalkyl groups may include S═O or SO ₂ ;
Heterocycloalkyl groups of alkyl, aryl, heteroaryl, spirocycloalkyl, spiroheterocycloalkyl, cycloalkyl, heterocycloalkyl and -C _1-6 alkyl-heterocycloalkyl groups of R ^a , R ^b , R ^c , and R ^d Is unsubstituted or substituted with H, OH, -N = N = N, halo, -C _1-6 alkyl, -OC _1-6 alkyl, C _1-6 haloalkyl, -O-haloC _1-6 alkyl, phenyl, 1, 2, 3, or 4 independently selected from tolyl, -C (O) C _1-6 alkyl, -C (O) OCH ₃ , SO ₂ -phenyl, or -SO ₂ -N (CH ₃ ) ₂ May be substituted with a R ¹⁴ substituent;
n is independently at each occurrence an integer of 1, 2, 3 or 4, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of its stereoisomer. The compound of claim 5, wherein the compound of formula I '
Formula I'a;

A compound having, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof. 7. A compound according to claim 5 or 6, wherein b is a double bond, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of stereoisomer thereof. 8. A compound according to any one of claims 5 to 7, wherein Z is C, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of stereoisomer thereof. 8. A compound according to any one of claims 5 to 7, wherein Z is N, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of stereoisomer thereof. The compound according to any one of claims 5 to 9, wherein Q is O, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of stereoisomer thereof. The compound according to any one of claims 5 to 10, wherein W is CR ^WA R ^WB , or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of stereoisomer thereof. The compound according to any one of claims 5 to 11, wherein R ^WA and R ^WB are both H, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of the stereoisomer thereof. . The compound of any one of claims 5-12, wherein R ¹ is a halo compound, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of stereoisomer thereof. The compound of claim 13, wherein R ¹ is Cl, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of stereoisomer thereof. 14. A compound according to any one of claims 5 to 13, wherein R ² is H, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of stereoisomer thereof. The pharmaceutically acceptable compound of any one of claims 5-15, wherein R ³ is H or —C _1-6 alkyl, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof. Possible salts. The compound of claim 16, wherein R ³ is —CH ₃ , or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of stereoisomer thereof. The compound of claim 16, wherein R ³ is H, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of stereoisomer thereof. 19. The compound of any of claims 5-18, wherein R ⁴ is H, -C _1-6 alkyl, -C _1-6 alkylhalo, -C _1-6 alkyl-OC _1-6 alkyl, or- (CH ₂ CH ₂ O) _n R ^a , -C _1-6 alkyl is unsubstituted or substituted -OH, (= O), phenyl, -O-SiR ^a R ^b R ^c , -NR ^a R ^b , 3- to 12-membered cycloalkyl, or a compound substituted with 3- to 12-membered monocyclic or bicyclic heterocycloalkyl having 1, 2, 3, or 4 heteroatoms independently selected from O, N or S , Or stereoisomers thereof, pharmaceutically acceptable salts thereof, or pharmaceutically acceptable salts of stereoisomers thereof. The compound of claim 19, wherein R ⁴ is H, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of stereoisomer thereof. The compound of claim 19, wherein R ⁴ is —C _1-6 alkyl, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of stereoisomer thereof. The compound of any one of claims 5-19 or 21, wherein R ⁴ is -CH ₃ , or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of the stereoisomer thereof. salt. The pharmaceutically acceptable compound of any one of claims 5-19, wherein R ⁴ is —CH ₂ CH ₂ OCH ₃ , or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof. salt. The pharmaceutically acceptable compound of any one of claims 5-23, wherein R ⁵ is H or —C _1-6 alkyl, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof. Possible salts. The compound of claim 24, wherein R ⁵ is —CH ₃ , or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of stereoisomer thereof. The pharmaceutically acceptable compound of any one of claims 5-25, wherein R ⁶ is H or —C _1-6 alkyl, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof. Possible salts. The compound of claim 26, wherein R ⁶ is H, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of stereoisomer thereof. The compound of any one of claims ^5-27 , wherein each of R ^4A , R ^5A , R ^6A , R ^7A and R ^8A is independently selected from H, OH, halo, or —C _1-6 alkyl, Or stereoisomers thereof, pharmaceutically acceptable salts thereof, or pharmaceutically acceptable salts of stereoisomers thereof. The compound of claim 28, wherein R ^4A , R ^5A , R ^6A , R ^7A and R ^8A are each H, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of stereoisomer thereof. . 30. The compound of any one of claims 5 to 29, wherein R ⁹ is H, -C _1-6 alkyl, -C _2-6 alkenyl, or -C _1-6 alkyl-OC _1-6 alkyl or -C A compound independently selected from _1-6 haloalkyl, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof. The compound of claim 30, wherein R ⁹ is H, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of stereoisomer thereof. The compound of claim 30, wherein R ⁹ is —CH ₃ , or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of stereoisomer thereof. The compound of claim 30, wherein R ⁹ is —CH ₂ CH ₃ , or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of stereoisomer thereof. 34. The compound of any of claims 5 to 33, wherein R ^9A is H, C _1-6 haloalkyl, C _1-6 alkyl, -C _2-6 alkenyl-(CH ₂ CH ₂ O) _n R ^a , -SO ₂ R ^a , -C (= O) R ^a , -C (= O) OR ^a , -C (= O) NR ^a R ^b , -NR ^a R ^b , -N = N = N,- C _1-6 alkyl-OC _1-6 alkyl, 6- to 12-membered aryl, 6- to 12-membered heteroaryl, 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, 3-membered To a 12-membered cycloalkenyl, a 3-membered to 12-membered monocyclic or bicyclic cycloalkyl, or a 3-membered to 12-membered monocyclic or bicyclic heterocycloalkyl group, and a heteroaryl, spiroheterocycloalkyl and heterocycloalkyl group Has 1, 2, 3, or 4 heteroatoms independently selected from O, N or S, and the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkyl groups may comprise a C═O group, Additionally spiroheterocycloalkyl and heterocyclo Kill group S = O or compounds that may contain SO _2, or a stereoisomer, chemical to allow its pharmaceutically acceptable salt, or pharmaceutically acceptable salt of the stereoisomer thereof. The group of claim 34, wherein the 3- to 12-membered monocyclic heterocycloalkyl R ^9A group is unsubstituted or substituted with OH, halo, —NR ^c R ^d , —C _1-6 alkyl, —C ₂ -C ₆ alkenyl, — C ₂ -C ₆ alkynyl, -OC _1-6 alkyl, -C _1-6 alkyl-OH, -C _1-6 alkyl-OC _1-6 alkyl, C _1-6 haloalkyl, -O-haloC _{1 -6} alkyl, -SO ₂ R ^c , -CN, -C (= 0) NR ^c R ^d , -C (= 0) R ^c , -OC (= 0) R ^a , -C (= 0) OR ^c , 6-membered to 12-membered aryl, 6-membered to 12-membered heteroaryl, 5-membered to 12-membered spirocycloalkyl or spiroheterocycloalkyl, 3-membered to 12-membered cycloalkenyl, 3-membered To a 12-membered monocyclic or bicyclic cycloalkyl, or a 1, 2, 3 or 4 R ¹⁰ substituents independently selected from 3-membered to 12-membered monocyclic or bicyclic heterocycloalkyl groups, heteroaryl, spirohetero Cycloalkyl, or heterocycloalkyl group has 1, 2, 3 or 4 heteroatoms independently selected from O, N or S, cycloalkyl , Spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkyl groups may comprise C═O groups, and further, spiroheterocycloalkyl and heterocycloalkyl groups may comprise S═O or SO ₂ , or compounds thereof Stereoisomers, pharmaceutically acceptable salts thereof, or pharmaceutically acceptable salts of stereoisomers thereof. The group of claim 35, wherein the 1, 2, 3 or 4 R ¹⁰ substituents are independently selected from —C _1-6 alkyl or a 3- to 12-membered monocyclic heterocycloalkyl group, wherein the heterocycloalkyl group is O, N or A compound having 1, 2, 3, or 4 heteroatoms independently selected from S, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of stereoisomer thereof. 37. The compound of any one of claims 34, 35 or 36, wherein R ^9A is -N = N = N,

Compounds or stereoisomers thereof, pharmaceutically acceptable salts thereof, or pharmaceutically acceptable salts thereof of stereoisomers selected independently from. The compound of claim 5, wherein the compound of formula I '
[Formula II ']

Wherein R ⁴ , R ⁵ , R ⁹ and R ^9A are compounds as defined above, stereoisomers thereof, pharmaceutically acceptable salts thereof, or pharmaceutically acceptable salts of stereoisomers thereof. The compound of claim 5, wherein the compound of formula I '
[Formula II'a]

Wherein R ⁴ , R ⁵ , R ⁹ and R ^9A are compounds as defined above, stereoisomers thereof, pharmaceutically acceptable salts thereof, or pharmaceutically acceptable salts of stereoisomers thereof. The compound of claim 5, wherein the compound of formula I '
Formula IV ';

Wherein R ⁴ , R ⁵ , R ⁹ and R ^9A are compounds as defined above, or stereoisomers thereof, pharmaceutically acceptable salts thereof, or pharmaceutically acceptable salts of stereoisomers thereof. The compound of claim 5, wherein the compound of formula I 'is
Formula IV'a;

Wherein R ⁴ , R ⁵ , R ⁹ and R ^9A are compounds as defined above, stereoisomers thereof, pharmaceutically acceptable salts thereof, or pharmaceutically acceptable salts of stereoisomers thereof. Compound having a structure selected from

Or stereoisomers thereof, pharmaceutically acceptable salts thereof, or pharmaceutically acceptable salts of stereoisomers thereof. The compound of claim 42 or a pharmaceutically acceptable salt thereof. The compound of claim 5, wherein the compound is

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

, or

Compounds selected from, stereoisomers thereof, pharmaceutically acceptable salts thereof, or pharmaceutically acceptable salts of stereoisomers thereof 45. The compound of claim 44 or a pharmaceutically acceptable salt thereof. A pharmaceutical composition comprising a compound of any one of claims 1-45, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or diluent. A method of treating cancer, the method comprising: administering to a patient in need thereof a therapeutically effective amount of a compound of any one of claims 1-46 or a pharmaceutically acceptable salt thereof. 48. The method of claim 47, wherein the cancer is a hematologic malignancy. 48. The method of claim 47, wherein the cancer is from the group consisting of breast cancer, colorectal cancer, skin cancer, melanoma, ovarian cancer, kidney cancer, lung cancer, non-small cell lung cancer, lymphoma, non-Hodgkin's lymphoma, myeloma, multiple myeloma, leukemia and acute myeloid leukemia The method chosen. The method of claim 49, wherein the cancer is multiple myeloma. 48. The method of claim 47, further comprising administering a therapeutically effective amount of a pharmaceutically active additional compound to the patient in need thereof. The method of claim 51, wherein the further pharmaceutically active compound is carfilzomib. The method of claim 51, wherein the further pharmaceutically active compound is Venetoclarks. The method of claim 51, wherein the further pharmaceutically active compound is cytarabine. 46. The use of a compound according to any one of claims 1 to 45 for treating cancer in a subject. 46. A compound according to any one of claims 1 to 45 in the manufacture of a medicament for treating cancer. The compound of claim 56, wherein the cancer is a hematologic malignancy. The cancer of claim 56 wherein the cancer is from the group consisting of breast cancer, colon cancer, skin cancer, melanoma, ovarian cancer, kidney cancer, lung cancer, non-small cell lung cancer, lymphoma, non-Hodgkin's lymphoma, myeloma, multiple myeloma, leukemia and acute myeloid leukemia Compound selected. 59. The compound of claim 58, wherein the cancer is multiple myeloma. 59. The compound of claim 58, wherein the cancer is acute myeloid leukemia. 59. The compound of claim 58, wherein the cancer is non-Hodgkin's lymphoma.

Images